Lisdexamfetaminsylat och prodrugs.

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Attention Deficit Hyperactivity and Disorders
Atten Defic Hyperact Disord. 2013; 5: 249-265.
Publicerad på nätet 6 april, 2013 doi: 10.1007 / s12402-013-0106-x
PMCID: PMC3751218<

Långverkande stimulantia för behandling av Attention Deficit / Hyperactivity Disorder: fokus på förlängd frisättning och prodrugen lisdexamfetaminedimesylate samt ta itu med fortsatta kliniska utmaningar
Frank A. López och Jacques R. Lerouxcorresponding, författare.

abstrakt
Dexamfetamin (d-AMP) genom lisdexamfetaminsylat (LDX) -administration.

Individer med attention-deficit / hyperactivity disorder (ADHD) har omfattande svårigheter i familjelivet, sig själv, skolan och/eller arbete, och funktionnedsättningen sträcker sig över hela dagen. Psykostimulantia är mycket effektiva läkemedel för behandling av ADHD, och utvecklingen av långverkande psykostimulerande har kraftigt ökat behandlingsalternativen för personer med ADHD. Strategier för utväcklingen av långtidsverkande stimulantia inkluderar kombinationen av omedelbar frisättning och fördröjd frisättning, och en osmotisk frisättning vid oralt intag. En ny utveckling är tillgången på den första prodrugen och centralt stimulerande, lisdexamfetaminedimesylate (LDX). LDX själv är inaktiv men klyvs enzymatiskt, främst i blodet, för att släppa d-amfetamin (d-AMP). Flera kliniska studier har visat att långverkande stimulantia är effektiva för att minska ADHD-symptom jämfört med placebo. Analoga och simulerade klassrum och vuxenstudier av arbetsmiljö har visat att långverkande stimulantia producerar symptom reduktion i minst 12 timmar. Långverkande stimulantia uppvisa liknande tolerabilitet och säkerhetsprofil som kortverkande medel. Även variationer i pH i magsäcken och motiliteten kan förändra tillgången och absorption av stimulantia som frigörs från långverkande formuleringar. Dexamfetamin genom LDX administration minskar sannolikheten att påverkas av gastrointestinala tillstånd. Således minskar inte den systemiska exponeringen. Långverkande preparat kan också ge minskad tilvänjning och ge lägre missbrukspotential jämfört med sina kortverkande motsvarigheter. Utvecklingen av långverkande stimulantia ger läkare med ett ökat utbud av medicinering alternativ för att skräddarsy behandling för personer med ADHD.

Nyckelord: ADHD-attention and hyperactivety disorder), centralstimulerande, amfetamin, metylfenidat, behandling, effekt, och säkerhet.

Inledning

Attention-deficit / hyperactivity disorder (ADHD) är ett vanligt neuropsykiatriskt tillstånd som beräknas omfatta 5-12% av barnen och som kvarstår i vuxen ålder i mer än hälften av fallen (Biederman och Faraone 2005; Polanczyk et al 2007.).
ADHD kännetecknas på kärnsymptomen av ouppmärksamhet, hyperaktivitet och impulsivitet (American Psychiatric Association 2000).
Dessutom uppvisar personer med ADHD funktionsnedsättningar som inkluderar svaga och eller svåra intrafamiliära interaktioner, låg akademisk prestation och konfliktfyllda sociala interaktioner hos barn och ungdomar, och ökad risk för lägre utbildningsnivå, atypska beteenden som leder till gripanden och trafikförseelser, arbetslöshet och skilsmässa hos vuxna (Able m fl 2007;. et al. Barkley 2006, et al. Biederman 2006a;. et al Kessler 2006, et al. Klassen 2004,. m.fl. Sawyer 2002).

Kliniska riktlinjer för behandling av ADHD rekommenderar generellt en individualiserad, multimodal plan som innehåller läkemedelsbehandling, beteendemässiga, och pedagogiska insatser (American Academy of Pediatrics 2011; kanadensiska Attention Deficit Hyperactivity Disorder Resource Alliance (CADDRA) 2011; Institutet för hälsa och Clinical Excellence 2009 ; Pliszka 2007).
Under många år har kortverkande psykoaktiva preparat av metylfenidat (MPH) och amfetamin (AMP) varit grunden för farmakologisk terapi vid. Men trots deras väldokumenterade effekt så har varaktighet och effekt begränsats av ett handlingsutrymma i intervaller på 3-6 h vilket ställer betydande utmaningar och begränsningar i behandling av ADHD (al. Antshel et 2011).
Kravet för upprepad dosering under dagen kan orsaka förlägenhet och stigmatisering för patienten, svårigheterna med att lagra schemalagda läkemedel, särskilt i en skolmiljö, fragmenteterat intag och potential för avledning av läkemedel för icke-medicinsk användning (Swanson 2003;. al Wolraich et 2001).
Som svar på dessa utmaningar, har långverkande CS (centralstimulerande) utvecklats för att lindra ADHD-symtom under hela dagen utan behov av upprepad dosering och för att ge en mer varaktig effekt jämfört med kortverkande medel (Adler och Nierenberg 2010; Christensen et al 2010;. Ramos-Quiroga . al et 2008;. al Spencer et 2011,. m.fl. van den Ban 2010).

Variationen i de farmakokinetiska egenskaperna för de olika beredningarna av långverkande psykoterapier återspeglas i deras farmakodynamiska egenskaper, inklusive deras debut, magnitud och varaktighet i symtomlindring. Behandlingsstrategier bör baseras på en förståelse av effekt och säkerhetsprofil för varje formulering, parat med individuella behov.
Långverkande psykostimulantia, samt icke-stimulerande atomoxetin, rekommenderas som första linjens läkemedelsbehandling i många länder för hantering av ADHD hos barn, ungdomar och vuxna (American Academy of Pediatrics 2011; kanadensiska Attention Deficit Hyperactivity Disorder Resource Alliance (CADDRA) 2011; Institutet för hälsa och Clinical Excellence 2009; Pliszka 2007).
Denna artikel kommer att granska de olika beredningarna av kontrollerad frisättning och prodrug- leveranssystem för långverkande stimulantia, samt undersöka effekterna av dessa beredninger på deras farmakokinetik, effekt, säkerhet och efterlevnad.

Långverkande stimulantia formuleringar

De långverkande psykostimulerande beredningarna som är godkända för behandling av ADHD kan kategoriseras enligt den teknik som har använts för att förlänga eller fördröja frisättningen av den aktiva substansen.

(bild. 1) (tabell (tabell 1) .1).

I den första generationen av långverkande stimulantia med fördröjd frisättning består av MPH (MPH-SR) som utnyttjade en vax-matris-baserad teknik för att leverera en enda utdragen puls av MPH. Med en verkningstid på upp till 8 timmar. Vissa beskriver de här beredningarna för medellång istället långverkande (Dopheide 2009), och deras effektivitet kan vara sämre än flera doseringsregimer för omedelbar frisättning (Swanson och Volkow 2009).
Den platta (noll-order) läkemedelstillförselprofilen för MPH-SR kan svara för utvecklingen av akut drogtolerans vid exponering för relativt höga läkemedelsnivåer under en längre period (Swanson 2003).

Fig. 1
Fig. 1

Tillförselsystem för långverkande psykostimulantia som används vid behandling av ADHD. Visas inte är leveranssystem för MPH-SR och Novo-MPH ER-C. MPH-SR är en formulering med förlängd frisättning i tablettform som använder ett vax-baserad matris för att uppnå långvarig …
Tabell 1
Tabell 1

Sammanfattning av medelvärde (SD) farmakokinetiska parametrarna för utvalda långverkande stimulantia

Flera beredningar med kontrollerad frisättning (CR) utvecklades som kombinerade en snabbt insättande effekt med utökad täckning över hela dagen. En strategi för den tvåfasiga leverans av stimulantia är att blanda kulor med olika läkemedelsfrisättningsprofiler. CR kapslar innehåller kulor som innehåller MPH (MPH-CR) eller d-AMP (AMP-CR) med distinkt omedelbar och fördröjd frisättning profiler (Fig. 1). CR-blandade amfetaminssalter innefattar lika delar av fyra AMP salter, d-AMP sackarat, D, L-AMP aspartat monohydrat, d-AMP sulfat, och D, L-AMP sulfat.
Varje kapsel innehåller omedelbar frisättning och enterodragerade kulor fördröjer frisättningen i ett 1: 1-förhållande (Shire Canada Inc .; Tulloch al et 2002.).
Flera stimulantia är baserade på kombinationer av kulor med omedelbar och förlängd frisättning profiler, men proportionerna av den totala dosen av aktiv beståndsdel i de två faserna av leverans är varierat.

En alternativ teknik utformad för att leverera den kontrollerade och bifasiskt leveransen av stimulerande läkemedel är den osmotiska frisättningen av orala systemet med metylfenidat (OROS-MPH).
Oros-MPH utnyttjar osmotiska trycket för att reglera hastigheten för leverans av den aktiva ingrediensen, racemisk MPH.
Varje kapsel består av en tre-avdelnings kärna som omges av ett semipermeabelt membran som i sin tur är omgiven av en läkemedelsbeläggningen (fig. 1).
Efter förtäring ger läkemedelsbeläggningen omedelbart frisläppande av MPH (22% av dosen) (McBurnett och Starr 2011).
Vatten vätska kommer in i osmotiska pumputrymmet från magtarmkanalen och levererar den återstående dosen vid en första ordningens hastighet från kärnan genom en laserborrad utgångsöppning (Janssen Inc .; et al. Swanson 2004). En koncentrationsgradient existerar mellan de två läkemedelsfack , som också modifierar hastigheten för läkemedelsfrisättningen.
Oros-MPH har en jämn stigande plasmakoncentrationsprofil, vilket är tänkt att minimera utvecklingen av akut tolerans och bibehålla full effekt hela dagen (Swanson et al. 2003).

Lisdexamfetaminedimesylate (LDX) är den första centralt stimulerande prodrugberedningen. Snarare än att använda en mekanisk eller fysikalisk mekanism för att uppnå en förlängd varaktighet av verkan, är LDX en prodrug där d-AMP är kovalent bunden till aminosyran lysin. LDX själv är terapeutiskt inaktiv men efter oral administrering, enzymatisk hydrolys av LDX frigörs den terapeutiskt aktiva delen d-AMP (Pennick 2010). Graden av enzymatisk omvandling styr den hastighet vid vilken d-AMP blir tillgänglig. Det resulterar i en farmakokinetisk profil som är dosproportionell och monofasisk samt återspeglar den gradvisa omvandlingen av LDX till d-AMP under perioden efter dosering (al. Boellner et 2010).
Enzymatisk hydrolys sker oftast i blodet (Pennick 2010)och den metaboliska omvandlingen av LDX till d-AMP är mindre sårbart av variationer i pH i magsäcken eller magtarmkanalen (Ermer m.fl. 2010b;. Et al. Haffey 2009; Krishnan och Zhang 2008). Således har farmakokinetiska studier visat att graden av d-AMP absorption och metabolism är mer konsekvent och förutsägbart mellan och inom individer med LDX än med förlängd frisättning blande amfetaminsalter (MAS-XR) (Biederman et al 2007a;. Ermer m.fl. . 2010a). Dessutom har graden av d-AMP leverans efter administrering av LDX rapporterats vara opåverkad av samtidig administrering av syrahämmande läkemedel omeprazol, medan en förkortad tid till maximal koncentration av d-AMP observerades när MAS-XR togs med omeprazol (Haffey et al. 2009) (tabell 1).

Effekten av långverkande stimulantia

Kliniska prövningar bevis stöder effekten av långverkande stimulantia. Tabellerna 2 och 33 presenterar en sammanställning av kortsiktiga (≤13 veckor), randomiserade, kontrollerade kliniska effektstudier av långverkande psykostimulantia.
Kontrollen av symtom under hela dagen och i den tidiga kvällen kommer sannolikt att vara en viktig faktor i den totala effekten av ADHD läkemedelsbehandling (Coghill m.fl.. 2008).

Tabell 2
Tabell 2

Korttids (≤13 veckor), randomiserade, kontrollerade kliniska effektstudier av långverkande metylfenidat baserade stimulantia hos barn och vuxna med ADHD

Tabell 3
Tabell 3
Korttids (≤13 veckor), randomiserade, kontrollerade kliniska effektstudier av långverkande amfetaminbaserade psykofarmaka hos barn och vuxna med ADHD.

Metylfenidat med fördröjd frisättning

Det finns begränsade data från kliniska studier för MPH-SR hos barn med ADHD (tabell 2). Vid en jämförelse av omedelbar frisättning MPH (MPH-IR), med MPH-SR, och kontrollerad frisättning av d-AMP och pemolin hos pojkar med ADHD. Fördröjd frisättning av MPH visade effekt jämfört med placebo i vissa beteendeåtgärder, vissa prestationsbaserade uppgifter och strukturerade bedömningar av rådgivare på förkortade Conners ‘Lärare Rating Scale (ACTRS), men inte på lärarskattad ACTRS (Pelham m.fl.. 1990). MPH-SR har en effektduration på cirka 8 timmar (Novartis Pharmaceuticals Canada Inc.).

Metylfenidat och kontrollerad frisättning

MPH-CR har visat signifikant effekt i att minska ADHD-symptom (tabell 2). Hos barn med ADHD, både MPH-CR och IR-MPH gav liknande, statistiskt signifikanta minskningar från baseline i Conners ‘Parent Rating Scale-Revised poäng (CPRS-R) (et al. Weiss 2007). Dock har överlägsen symtomminskning med IR-MPH kontra MPH-CR observeras utifrån Conners ‘Teacher Rating Scale-Revised (CTR-R).
Hos vuxna med ADHD,gav MPH-CR signifikant bättre Kliniska Globala Intryck-Improvement (CGI-I) -betyg jämfört med placebo efter 2 veckor (Jain et al. 2007).
Med hjälp av ett analog crossover klassrumsprotokoll, Schachar et al. (2008) jämfördes MPH-CR och IR-MPH med placebo hos barn med ADHD. Signifikanta förbättringar jämfört med placebo sågs med MPH-CR i upp till 10 timmar efter dosering, baserad på förändring från baseline på Ouppmärksamhet / Överaktivitet Med Aggression-Conners ‘skala (IOWA-C) totalt och delpoäng för ouppmärksamhet / överaktivitet och aggression / trots .

Osmotisk frisättning av orala system med metylfenidat

Oros-MPH har visat effekt i ADHD symptom minskning av barn, ungdomar och vuxna (tabell 2). I en 4-veckors studie med parallella grupper och placebokontroll, var OROS-MPH signifikant effektivare än placebo hos barn med ADHD, utifrån endpoint betyg för Ouppmärksamhet / Överaktivitet skalan för IOWA Conners ‘Teacher Rating Scale (Wolraich et al. 2001).
I en 2-veckors, parallellgruppstudie så minskade OROS-MPH signifikant ADHD Rating Scale IV (ADHD-RS-IV)- poäng på ungdomar med ADHD jämfört med placebo (Wilens et al. 2006a).
Liknande symtomförbättringar jämfört med placebo har beskrivits hos vuxna som behandlas med OROS-MPH (Adler et al 2009;. Et al. Biederman 2006b; Medori et al 2008.).

I en head-to-head studie kunde subtila variationer av tidpunkt och omfattning av symtomkontroll observeras mellan MPH-CD och Oros-MPH. Även om MPH-CD visade större effekt under morgontimmarna så uppvisade OROS-MPH mer långvariga effekter, som sträcker sig upptill 12 timmar efter en enda morgondos (et al. Pelham 2001).
I Head-to-head jämförelser av långverkande MPH (MPH-LA) och Oros-MPH hos barn med ADHD med hjälp av det analoga klassrumprotokollet över 8-12 h har båda aktiva behandlingarna förbättrat ”Permanent Product”-måttet (PERMP) av matteprovresultat (PERMP-C) (Lopez et al. 2003) tillika vid Swanson, Kotkin, Agler, M-Flynn och Pelham Rating Scale (SKAMP)- skattning av uppmärksamhet (Silva et al. 2005 ). Båda behandlingarna var allmänt effektiva och väl tolererade. Skillnader i resultaten vid laboratorieskolmiljöer utgjörd av de preparat med den högsta förväntade plasma MPH koncentration över efterdoseringsperioden (Swanson et al. 2004). Placebokontrollerade analoga klassrumstudier tyder på att Oros-MPH har en verkningstid på minst 12,5 timmar (sista gången punkten bedömas) hos barn med ADHD (et al Armstrong 2012,.. Murray et al 2011;. Wigal et al 2011 ).

Blandade amphetaminesalt förlängd frisättning

Flera randomiserade kontrollerade kliniska prövningar har visat att kontrollerad frisättning MAS (MAS-CR) är effektivt jämfört med placebo för att minska ADHD-symptom hos barn, ungdomar och vuxna (tabell 3) (Biederman et al 2002;. Spencer et al 2006b. . m.fl. Weisler 2006). En analog klassrumstudie på barn visade en signifikant effekt av MAS-CR jämfört med placebo framkom vid 1,5 timmar efter dosering och kvarstod i upp till 12 timmar, baserat på förbättringar från utgångsvärdet vid slutpunkten i SKAMP-D och matte provresultat (al. McCracken et 2003).

Dextroamfetamin kontrollerad frisättning

Studier av effekten av kontrollerad frisättning AMP (AMP-CR) hos deltagare med ADHD är begränsade.
Pelham et al. har jämfört behandlingarna med AMP-CR, IR-MPH, MPH-SR, och pemolin hos pojkar.
Även om alla behandlingar var bättre än placebo i vissa beteendemönster, så var endast pemolin och AMP-XR bättre än placebo vid lärarskattad ACTRS. Varaktigheten av effekten karakteriserades som inom 2 timmar efter intag och upp till 9 timmar efter dosering (Pelham m.fl.. 1990). I en analog klassrummet studie av AMP-CR hos barn påvisas förbättrade resultat av objektiva actometrar, åtgärder och humörsvägningar jämfört med placebo 1,75-12 timmar efter en enda morgondos. Effekterna av AMP-CR var ”mindre robust” än IR-MAS under morgontimmarna efter dosering men förlängdes 3-6 timmar längre (James et al. 2001).

lisdexamfetaminedimesylate

Effekten av LDX jämfört med placebo för att minska symptomen på ADHD har påvisats hos patienter över hela livslängden (tabell 3).
I 4-veckors studier med LDX 30, 50, och 70 mg hos barn, ungdomar och vuxna med ADHD, alla doser av LDX visat signifikanta förbättringar i ADHD-RS-IV poäng jämfört med placebo (Adler et al 2008;. Biederman et al 2007b;.. al Findling et 2011).
Andelen svar (definierat som> 30% förbättring av ADHD-RS-IV poäng och CGI-I betyg av mycket bättre eller mycket bättre) var ca 80% vid slutpunkten hos barn som behandlats med LDX 70 mg jämfört med mindre än 20 % för placebo (Biederman et al. 2007b).
Vidare förbättringar jämfört med placebo i CPRS-R poäng hos barn med ADHD bibehölls fram till 18:00 efter en tidig morgondosen (Biederman et al. 2007b). I en analog klassrumstudie på barn med ADHD påvisas att de terapeutiska effekterna av LDX utvidgas 1,5-13 h efter dosering (de första och sista tidpunkter bedömts) baserad på förbättringar av SKAMP och PERMP poäng (Wigal et al. 2009).
I en simulerad vuxen arbetsmiljöstudie var de terapeutiska effekterna av LDX verksamma i 2-14 timmar efter dosering (den första och sista analystillfällen) hos vuxna med ADHD, vilket framgår av förbättringar i PERMP poäng jämfört med placebo (Wigal m.fl. . 2010). Demonstrationen att effekten av LDX bibehålls i minst 13 timmar hos barn och 14 timmar hos vuxna tyder på att denna prodrug kan vara den längst verkande centralstimulerande behandling för ADHD.

Metaanalyser av effektiviteten av långverkande stimulantia

Metaanalyser har jämfört effektresultat från flera studier av olika stimulantia formuleringar (Faraone 2009, 2012; Faraone och Glatt 2010). I en analys av 32 studier med 16 mediciner i ungdomar med ADHD, den genomsnittliga effektstorleken för långverkande stimulantia var 0,95 jämfört med 0,99 för omedelbar frisättning stimulantia (Faraone 2009). Även i 19 studier av 13 ADHD-droger hos vuxna, menar effektstorlekar var 0,73 och 0,96 för långverkande och omedelbar frisättning stimulantia, respektive (Faraone och Glatt 2010). En metaanalys av effektstudier hos barn med ADHD, baserat enbart på ADHD Rating Scale och Clinical Global Impressions resultat, funnit att en sammanslagen effektstorlek för LDX på cirka 1,5 var signifikant (p <0,001) större än den sammanslagna effekten storlek andra mediciner (Faraone 2012). I studier på vuxna, LDX effektstorlekar liknade dem av andra mediciner. Använda nummer-behövs-to-treat (NNT) för att jämföra effekten av stimulantia mediciner över 23 kliniska studier på barn och ungdomar, NNT (95% konfidensintervall) var något lägre (dvs färre patienter krävdes för att se en positiv effekt) för formuleringar av AMP (2,0 [1,7, 2,2]) än MPH (2,6 [2,4, 2,8]), även om medel NNT-värden inte beräknades för långverkande och omedelbar frisättning (al. Faraone et 2006). Säkerhet för psykostimulantia
Kort och långverkande psykostimulanter har liknande profiler negativ händelse (Banaschewski et al. 2006). Biverkningar som oftast förknippas med användningen av psykostimulantia för behandling av ADHD innefattar neurologiska (huvudvärk, yrsel, sömnsvårigheter, kramper), psykiatriska (humör / ångest, tics, psykos) och gastrointestinal (buksmärta, dålig aptit som leder till viktminskning / saktat tillväxt) effekter. I allmänhet är dessa symtom milda och / eller tillfällig (Graham et al. 2011). Områden av särskilt intresse i användningen av psykostimulantia för behandling av ADHD inkluderar deras effekter på tillväxt och kardiovaskulära parametrar och deras potential för missbruk.

Effekt på vikt och tillväxt

En analys av 20 longitudinella studier fann att långvarig psyko barn med ADHD resulterade i statistiskt signifikanta förseningar i tillväxt kontra åldersrelaterade normer (Faraone et al. 2008). Effekter tycktes vara dosberoende, var tydligare för vikt än höjd, var liknande mellan MPH och AMP formuleringar, och, i många fall, tycktes normalisera tiden trots fortsatt behandling (al. Faraone et 2008). I MTA (Multimodal Treatment Study of Children with ADHD), den största longitudinell studie av barn med ADHD, var genomsnittliga relativa storleken på patienten (en blandning av längd och vikt som z poäng) ett negativt samband med den genomsnittliga kumulativa exponering för psykostimulantia. Tillväxten mattas för nyligen medicinerad kontra obehandlade deltagare hittades under de första 14 månaderna, försvagades vid 24 månader, och var icke-signifikant vid 36 månader (Murray et al 2008;. Swanson et al 2007.). Ändå rekommenderas att längd och vikt övervakas hos patienter som får stimulerande läkemedel, inklusive långverkande formuleringar.

Kardiovaskulära händelser

Kardiovaskulära säkerhetsproblem med psykostimulantia ADHD mediciner höjdes utifrån sällsynta fall av plötslig död och andra hjärthändelser (Vetter et al. 2008). Psyko modulera hjärt kontraktilitet och hjärtfrekvens via sympatomimetiska effekter (Wilens et al. 2006b), och förändringar av vitala tecken har noterats med MPH och AMP behandlingar, inklusive ökningar av systoliskt och diastoliskt blodtryck (~ 2-6 mmHg) och hjärtfrekvens (~ 8 slag per minut) (et al. Wilens 2005). I kliniska studier på psyko hos barn och vuxna, inga kliniskt signifikanta förändringar av atrial eller ventrikulär överledning eller repolarisation har observerats (Wilens et al. 2006b). En ökad risk för hjärtrelaterade akutbesök med nuvarande psyko användning och icke-användning har rapporterats (et al Winterstein 2007;.. Al Winterstein et 2009), men i de flesta friska barn som inte tidigare eller nuvarande kardiovaskulära missbildningar, psyko producerade kardiovaskulära effekter av minimal klinisk betydelse (m.fl. Findling 2001, 2005;. Safer 1992;. Wilens et al 2006b). Likaså ingått en lång, retrospektiv, populationsbaserad kohortstudie att ADHD medicinering till barn och unga och medelålders vuxna inte var associerad med en ökad risk för allvarliga kardiovaskulära händelser jämfört med icke-användning (Cooper et al 2011;. Habel et al. 2011). Men när behandling med något psyko formulering övervägs i en patient med strukturell hjärtsjukdom, eller i en patient som har en personlig eller en familjehistoria av synkope eller plötslig död, respektive, en pediatrisk eller kardiologisk samråd före ADHD farmakologisk behandling är starkt rekommenderas (Graham et al. 2011).

Missbruk, felanvändning och avledning

Receptbelagda stimulantia klassificeras som kontrollerade ämnen och deras missbruk, felaktig användning, och avledning är viktiga för folkhälsan och säkerhetsproblem (Kollins 2008;. Wilens m fl 2008). Eftersom eufori och drog ”gilla” är kopplade till en snabbare absorptionshastighet och leverans till hjärnan (Volkow och Swanson 2003) följer att styra graden av stimulerande frisättning får ändra sin potential för missbruk. Stöd för en lägre missbrukspotential för långverkande jämfört med kortverkande stimulantia inkluderar större subjektiva svar för omedelbar frisättning stimulantia än Oros-MPH hos friska vuxna (et al Parasrampuria 2007;. Spencer et al 2006a.). Formuleringen av stimulantia som en gång dagligen mediciner minskar också sannolikheten för avledning genom att ta bort kravet på läkemedelsadministrering i skolan.

Många långverkande stimulantia kan manipuleras för att underlätta en snabbare absorption av den aktiva beståndsdelen, t.ex. genom att krossa eller upplösning av mediciner för att underlätta intranasal eller parenteral administration (Mao et al. 2011). Men de fysiska egenskaperna hos stimulantia formuleringar, till exempel icke-deformerbara skal av OROS-MPH kapsel kan göra dem svårare att bryta, skära eller krossa. Prodrugen design LDX innebär att andelen aktiva d-AMP frisättningen begränsas av graden av enzymatisk omvandling, oavsett vägen läkemedelsadministrering eller kapsel intactness. Således är plasmakoncentration-tidsprofilen för intranasal LDX hos friska män som liknar den som efter oral administrering (Ermer et al. 2011). Hos personer med en historia av stimulantia missbruk, poängen i Drug Rating Questionnaire-Angående smak skala för oral LDX (≤100 mg) var inte annorlunda med placebo, medan motsvarande oral dos av d-AMP (40 mg) gynnades jämfört med placebo (Jasinski och Krishnan 2009a). På samma sätt, till skillnad från intravenös d-AMP 20 mg, motsvarande intravenös dos av LDX (50 mg) producerade inte subjektiva missbruksrelaterade gilla poäng (Jasinski och Krishnan 2009a, b).

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Vidhäftning
Icke-följsamhet till medicinering för kroniska sjukdomar uppskattas till ca 50% (World Health Organization 2003). I ADHD, är förekomsten av medicinering avbrytande eller avsteg rapporteras variera från 13 till 64% (Adler och Nierenberg 2010). Efter 14 månaders behandling med MPH i MTA studien, analys av salivprover visade att endast 53,5% av patienterna var vidhäftande vid varje analyspunkt och att nästan 25% av patienterna var icke vidhäftande vid 50% eller mer av sina analyser (Pappadopulos et al. 2009). Studier som har undersökt effekten av formuleringen på vidhäftning och ihållande stimulerande läkemedel för ADHD inkluderar flera retrospektiva påståenden analyser (Christensen et al 2010;. Et al. Marcus 2005, et al. Sanchez 2005). Den största av dessa identifierade över 60.000 nyligen behandlade patienter med ADHD (Christensen et al. 2010). Denna analys visade att medelvärdet (SD) vidhäftning (definierad som förhållandet mellan det antal dagar terapi tillföres till det totala antalet dagar persistenta) till långverkande stimulantia (0,56 [0,32]) var signifikant större (p <0,0001) än att för kort (0,43 [0,35]) och mellanliggande verkande (0.47 [0.35]) stimulantia. Likaså medelvärdet (SD) uthållighet (definierat som antalet dagar av 365 dagar plus index dag som patienten kvar på deras index terapi) på långverkande stimulantia (239,5 [145,8]) var signifikant större (p <0,0001 ) än för kort (186,7 [154,8]) eller medellångverkande (185,6 [153,4]) stimulantia (Christensen et al. 2010). Dessutom hittade ett diagram översyn av spanska vuxna med ADHD att övergången från kortverkande MPH till långverkande MPH var associerad med en signifikant förbättring i alla poster i förenklad medicinering följsamhet Questionnaire (Ramos-Quiroga et al. 2008). Dessa data tyder på att valet av formuleringen har viktiga konsekvenser för vidhäftning och ihållande ADHD stimulerande läkemedel. Gå till: Behandling individualisering Evidensbaserade riktlinjer ADHD inser att medicinering strategier bör skräddarsys för den enskilde. Bland de faktorer att beakta när man väljer en lämplig medicin för en patient med ADHD är drog klass och formuleringen krävs för att ge den önskade farmakokinetiska och farmakodynamiska profilerna. Valet av mediciner för ADHD inkluderar både stimulantia och icke-stimulantia. När det gäller stimulantia, även om medel svar på MPH och AMP är liknande, kan individer reagerar olika på de två läkemedlen. Som granskats av Arnold (2000), kommer ca 28% svarar företrädesvis till AMP, kommer 17% svarar företrädesvis till MPH, och mindre än 13% svarar inte heller (Arnold 2000). Där stimulerande läkemedel anges, bör valet av formulering baseras både på kliniska behov och preferenser patienten och / eller deras familj. Kort- och långverkande formuleringar ger behandlingsalternativ som sträcker sig från cirka 4 timmar till, när det gäller LDX, mer än 13 timmar hos barn (Wigal et al. 2009) och mer än 14 timmar hos vuxna (Wigal et al. 2010) . Det är viktigt att notera att suboptimalt svar på en klass eller formulering av stimulerande förutsäger inte fel i en annan. Således fann en nyligen post hoc-analys att den kliniska effekten och skattesatserna för remission hos barn med ADHD som behandlades med LDX var liknande hos patienter med en tidigare suboptimalt svar på MPH behandling till de av den totala studiepopulationen (Jain et al. 2011 ). Gå till: slutsatser Utvecklingen av kontrollerad frisättning av stimulantia och stimulerande prodrug LDX har kraftigt ökat antalet farmakologiska behandlingsalternativ för patienter med ADHD. På motsvarande systemiska exponering, effekten och säkerheten av långverkande stimulantia verkar vara likvärdiga med kortverkande formuleringar. Men långverkande mediciner erbjuder flera potentiella fördelar för patienterna. Långverkande stimulantia ger effekt i minst 13-14 timmar utan förstärkning. Bekvämligheten med dosering en gång dagligen kan bidra till förbättrad vidhäftning av långverkande stimulantia jämfört med kortverkande stimulantia. Prodrug tekniken kan också ge lägre mellan och inom variabiliteten i exponering än mekaniska kontrollerad frisättning system. Vidare kan långverkande stimulantia vara mindre benägna att missbruka än sina kortverkande motsvarigheter. Således ger utvecklingen av långverkande formuleringar av stimulantia viktiga ytterligare behandlingsalternativ för hantering av ADHD. Gå till: erkännanden Författarna vill hedra sin avlidne kollega, Atilla Turgay, MD, och erkänna hans bidrag till tidigare utkast till denna artikel. Innehållet i detta manuskript, den ultimata tolkningen, och beslutet att lämna in den för publicering i ADHD Attention Deficit och hyperaktivitet Disorders gjordes självständigt av författarna. Skriva och redigera stöd för detta manuskript lämnades av Ogilvy CommonHealth Scientific Communications och Oxford PharmaGenesis ™ Ltd och finansieras av Shire Development LLC. Jäv Frank A. López, MD, är konsult för Bristol-Myers Squibb, Celltech, Cephalon, Eli Lilly, New River Pharmaceuticals, Novartis, Pfizer och Shire USA; har fått bidrag / forskningsstöd från Bristol-Myers Squibb, Celltech, Cephalon, Eli Lilly, New River Pharmaceuticals, Novartis, Pfizer och Shire; är på högtalarna presidiet för Cephalon, Novartis och Shire; och är ett rådgivande styrelseledamot för Celltech, Cephalon, Eli Lilly, Novartis och Shire. Jacques R. Leroux, MD, är konsult eller högtalare för Canadian Psychiatric Association, Eli Lilly, Janssen Ortho, Le regroupement PANDA, Purdue Pharma och Shire. 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Articles from Springer Open Choice are provided here courtesy of Springer CNS Drugs. 2014;28: 497–511. Published online May 1, 2014. doi: 10.1007/s40263-014-0166-2 PMCID: PMC4057639 A Systematic Review of the Safety of Lisdexamfetamine Dimesylate David R. Coghill,corresponding author Beatriz Caballero, Shaw Sorooshian, and Richard Civil Author information ► Copyright and License information ► Gå till: abstrakt bakgrund Here we review the safety and tolerability profile of lisdexamfetamine dimesylate (LDX), the first long-acting prodrug stimulant for the treatment of attention-deficit/hyperactivity disorder (ADHD). Metoder A PubMed search was conducted for English-language articles published up to 16 September 2013 using the following search terms: (lisdexamfetamine OR lisdexamphetamine OR SPD489 OR Vyvanse OR Venvanse OR NRP104 NOT review [publication type]). Resultat In short-term, parallel-group, placebo-controlled, phase III trials, treatment-emergent adverse events (TEAEs) in children, adolescents, and adults receiving LDX were typical for those reported for stimulants in general. Decreased appetite was reported by 25–39 % of patients and insomnia by 11–19 %. The most frequently reported TEAEs in long-term studies were similar to those reported in the short-term trials. Most TEAEs were mild or moderate in severity. Literature relating to four specific safety concerns associated with stimulant medications was evaluated in detail in patients receiving LDX. Gains in weight, height, and body mass index were smaller in children and adolescents receiving LDX than in placebo controls or untreated norms. Insomnia was a frequently reported TEAE in patients with ADHD of all ages receiving LDX, although the available data indicated no overall worsening of sleep quality in adults. Post-marketing survey data suggest that the rate of non-medical use of LDX was lower than that for short-acting stimulants and lower than or equivalent to long-acting stimulant formulations. Small mean increases were seen in blood pressure and pulse rate in patients receiving LDX. slutsatser The safety and tolerability profile of LDX in individuals with ADHD is similar to that of other stimulants. Gå till: Viktiga punkter Table thumbnail Gå till: Inledning Stimulants are recommended by European and North American guidelines as a first-line medication option for children and adolescents (aged 6–17 years) with attention-deficit/hyperactivity disorder (ADHD) [1–3], and are also recommended in some guidelines for the treatment of adults with the disorder [2, 4]. A range of amphetamine (AMP)- and methylphenidate (MPH)-based stimulants, as well as the non-stimulants atomoxetine (ATX), guanfacine, and clonidine, are available for the treatment of ADHD in North America and several European countries [5]. Numerous studies have shown stimulants to be effective in reducing the core symptoms and behavioral impairments associated with ADHD [1, 6]. In a meta-analysis of 32 double-blind, placebo-controlled trials of ADHD medications in patients aged 6–18 years, effect sizes were shown to be significantly greater for stimulants than for non-stimulants [7]. A second meta-analysis of 23 double-blind, placebo-controlled trials of stimulant medications for ADHD in children and adolescents found that effect sizes compared with placebo were modestly but statistically significantly greater for AMP-based stimulants than for MPH [8]. Various long-acting AMP- and MPH-based stimulants have been developed, with the aim of relieving ADHD symptoms throughout the day using a once-daily dose [9]. Lisdexamfetamine dimesylate (LDX) is the first long-acting prodrug stimulant for the treatment of ADHD [10]. After ingestion and absorption, LDX is enzymatically hydrolyzed to release the therapeutically active moiety d-AMP, and the essential amino acid lysine [11]. As hydrolysis of LDX occurs mainly in the blood, the generation of d-AMP is unlikely to be affected by either gastrointestinal pH or transit time [12–14]. Pharmacokinetic studies in humans have shown that exposure to d-AMP following oral administration of LDX is monophasic, sustained, and dose-proportional, with low intra- and inter-patient variability [12, 15, 16]. This profile of systematic exposure to d-AMP facilitates dose optimization by reducing the likelihood of sub- or supra-therapeutic levels [17]. The pharmacodynamic properties of LDX are reflected in clinical analog classroom studies and simulated adult workplace studies that have shown that, following a single dose of LDX, therapeutic effects are observed through to the last assessment of the day; 13 h post dose in children and 14 h post dose in adults [18, 19]. In a series of randomized, controlled trials, effect sizes for LDX have been shown to be greater than those for MPH-based stimulants in the treatment of children and adolescents with ADHD [8], and a post hoc analysis of data from a randomized, placebo- and active-controlled phase III clinical trial showed that improvements in the symptoms of ADHD were statistically significantly greater in patients receiving LDX than in those receiving the reference therapy osmotic-release oral system MPH (OROS-MPH) [20]. The safety warnings for LDX are similar to those for other stimulant treatments for ADHD [21]. In this review, we examine the safety and tolerability profile of LDX. We begin by analyzing the treatment-emergent adverse events (TEAEs) and vital signs data recorded in clinical trials of LDX, of both short- and longer-term duration. We then focus down on evidence relating to four specific safety concerns associated with stimulant ADHD pharmacotherapies, namely reduced weight and growth, sleep disruption, abuse liability, and cardiovascular events [3, 5, 22]. Gå till: Metoder A PubMed search was conducted using the following search terms: (lisdexamfetamine OR lisdexamphetamine OR SPD489 OR Vyvanse OR Venvanse OR NRP104 NOT review [publication type]). The final iteration of the search was conducted on 16 September 2013. The search was not limited by publication date but was limited to English language articles. The above search terms were subsequently used in conjunction with the following additional terms (applied individually): AND ADHD, AND abuse liability, AND cardiovascular safety, AND sleep, AND weight, AND growth. Of 129 references identified, 35 contained LDX safety and tolerability data in patients with ADHD (Fig. 1). Fig. 1 Fig. 1 Systematic review flowchart to identify safety outcomes reported in lisdexamfetamine dimesylate clinical trials. ADHD attention-deficit/hyperactivity disorder Gå till: Resultat Safety and Tolerability in Short-Term Trials Randomized, Parallel-Group, Double-Blind Trials in Patients with Attention-Deficit/Hyperactivity Disorder (ADHD) The efficacy and safety of LDX in the treatment of ADHD were evaluated in six randomized, parallel-group, double-blind, phase III trials (Table 1) [23–28]. Three trials (studies 301, 303, and 305), were forced-dose titration studies in which patients were randomized to receive once-daily LDX 30, 50, or 70 mg, or placebo for 4 weeks [23, 24, 26]. In these trials, dose increases followed a predefined schedule: patients randomized to LDX 30 mg received this dose throughout the study; patients randomized to LDX 50 mg received 30 mg/day during week 1 and 50 mg/day during weeks 2–4; patients randomized to LDX 70 mg received 30 mg/day during week 1, 50 mg/day during week 2, and 70 mg/day during weeks 3–4. The remaining three trials utilized dose-optimization protocols: study 403 was placebo controlled, study 325 was placebo and active (OROS-MPH) controlled, and study 317 was a head-to-head comparison of LDX and ATX. In these studies, patients randomized to LDX were individually optimized to LDX 30, 50, or 70 mg/day during weeks 1–4 based on efficacy and tolerability [25, 27, 28]. Patients randomized to the reference treatment OROS-MPH in study 325 were individually optimized to 18, 36, or 54 mg/day (OROS-MPH was administered according to European regulations with a maximum licensed dose of 54 mg/day) [25]. Patients randomized to the control treatment ATX in study 317 were optimized to 0.5–1.2 mg/kg (with a maximum daily dose of 1.4 mg/kg) if under 70 kg in weight, or 40, 80, or 100 mg/day in patients weighing 70 kg or over [27]. Tabell 1 Tabell 1 Most frequently reported treatment-emergent adverse events in randomized, double-blind, parallel-group clinical trials of lisdexamfetamine dimesylate [23–28] The overall rates of TEAEs for LDX-treated patients were generally similar across age groups and were typical of those previously reported for stimulants in general [3, 5, 22]. The overall frequency of TEAEs for LDX-treated patients did not differ greatly between studies with durations of 4 weeks or 7–10 weeks (Table 1). This may have been because most TEAEs are reported to occur within 4 weeks of treatment initiation [18, 19, 23, 24, 29, 30]. It is also possible that the dose-optimized design of studies 317, 325, and 403 may have reduced the rate of TEAEs compared with the forced-dose titration design of the three shorter trials. The most common TEAEs reported in patients receiving LDX in these short-term trials are shown in Table 1. In all studies, decreased appetite was the most common TEAE and was reported by ≥25 % (range 25.2–39.0) of patients treated with LDX, irrespective of age. Weight loss was reported in 9.2–21.9 % of children and adolescents receiving LDX, but was not consistently reported as a common TEAE in adult studies. Anorexia was reported in 10.8 % of children and adolescents receiving LDX in study 325 but by 5.1 % or less in the adult studies. Insomnia was common in all age groups, occurring in 11–19 % of LDX-treated patients. Dry mouth was a prominent TEAE in adults treated with LDX (25.7–31.6 %) but was reported in <7 % of children and adolescents. Nausea was reported in 2.5–12.5 % of patients receiving LDX. Although headache and nasopharyngitis were commonly reported TEAEs, their frequency did not differ greatly between the LDX and placebo groups in any trial. With regard to active treatment controls, headache, decreased appetite, and nasopharyngitis were reported by more than 10 % of patients receiving OROS-MPH in study 325, and decreased appetite, fatigue, headache, nausea, and somnolence were reported by more than 10 % of patients receiving ATX in study 317. Across all studies, the percentage of patients who discontinued treatment owing to a TEAE ranged from 4.3 to 9.2 % in the LDX treatment groups, compared with 1.3–3.6 % in the placebo groups, 7.5 % in the ATX group of study 317, and 1.8 % in the OROS-MPH group of study 325 (Table 1). In the placebo-controlled studies, TEAEs leading to discontinuation in at least 1 % of patients receiving LDX were as follows: ventricular hypertrophy as determined by electrocardiography (ECG), tic, vomiting, psychomotor hyperactivity, insomnia, and rash in study 301 in children; irritability, decreased appetite and insomnia in study 305 in adolescents; insomnia, tachycardia, irritability, hypertension, headache, anxiety, and dyspnea in study 303 in adults; and rectal fissure, fatigue, irritability, influenza, and decreased libido/erectile dysfunction also in adults [21, 23, 28]. In the ATX-controlled study in children and adolescents (study 317), the TEAEs leading to discontinuation were agitation, decreased weight, excoriation, indifference, irritability, somnolence, nausea, and tic in the LDX group, and headache, irritability, epigastric discomfort, fatigue, influenza, malaise, nausea, sedation, somnolence, and upper abdominal pain in the ATX group [27]. In the placebo- and OROS-MPH-controlled study 325, the TEAEs leading to discontinuation were vomiting, anorexia, decreased appetite, angina pectoris, tachycardia, decreased weight, and insomnia in the LDX group, and decreased appetite, irritability, and insomnia in patients treated with OROS-MPH [25]. The case of angina pectoris was a 13-year-old boy who experienced pre-cardiac pain that was considered by the study investigator to be of moderate intensity and did not meet the criteria for a serious TEAE. During the study, this patient had no clinically significant laboratory abnormalities, no treatment or concomitant medications were reported, and all ECGs were normal [25]. No deaths were reported in any of the studies. Serious TEAEs (defined as those that resulted in death, were life threatening, required hospitalization or prolongation of hospitalization, resulted in persistent or significant disability or incapacity, caused congenital abnormality or birth defect, or were considered an important medical event) were reported in two studies. In study 303, there were two serious TEAEs in adults receiving LDX (leg injuries following an automobile accident and post-operative knee pain) but neither were judged to be related to study treatment [23]. Serious TEAEs reported in children and adolescents in study 325 were syncope, gastroesophageal reflux disease, and appendicitis in the LDX group; loss of consciousness, hematoma, and clavicle fracture in the placebo group; and syncope and overdose in the OROS-MPH group [25]. Of these, only the case of overdose in a patient receiving OROS-MPH was considered to be related to study drug. This patient inadvertently took two doses of OROS-MPH on the same day and experienced a non-serious episode of initial insomnia; the overdose was reported to be mild in severity, was resolved, and did not result in a change of dosage or treatment (data on file). It was a requirement of the study 325 protocol that all reported instances of syncope were classified as serious TEAEs, regardless of the intensity or medical significance of the event. As is typical for stimulant medications, LDX treatment was associated with small mean increases in blood pressure (BP) and pulse rate compared with placebo in all age groups, with the largest mean increases seen with LDX 70 mg (Table 2) [17, 23, 25–28]. LDX treatment was generally not associated with any clinically relevant changes in mean ECG parameters, including corrected QT interval, although clinically meaningful post-baseline ECG findings were observed at week 1 in two adolescent patients receiving LDX in one of the forced-dose studies (QT interval corrected by Fridericia’s formula [QTcF] of 479 and 413 ms, respectively), which led to study drug discontinuation; no other clinically concerning trends in ECG interval assessments were observed [26]. While mean changes in vital signs and ECG parameters were generally not considered to be clinically meaningful, as shown in Table 3, small numbers of patients in studies 317 (children and adolescents), 305 (adolescents), and 303 (adults) were reported to meet outlier criteria for various cardiovascular parameters at least once during the study, supporting the need for careful monitoring of patients during treatment [23, 26, 27, 31]. However, few patients met outlier criteria at more than two study time points (study 303) or at 2 consecutive weeks (study 305) (Table 3), suggesting that the cardiovascular effects of treatment were not sustained [26, 31]. Table 2 Table 2 Changes from baseline to endpoint in vital signs in randomized, parallel-group, double-blind clinical trials Table 3 Table 3 Published outlier analyses of changes in vital signs and electrocardiogram parameters in randomized, parallel-group, double-blind clinical trials Crossover and Open-Label Trials In addition to the double-blind, parallel-group trials described above, LDX has also been studied in four short-term, placebo-controlled, crossover studies (two in children, one in college students, and one in adults) and two short-term open-label studies (both in children) [18, 19, 32–35]. In all six trials, patients met Diagnostic and Statistical Manual of Mental Disorders, fourth revision, text revision (DSM-IV-TR) diagnostic criteria for ADHD. In study 201, children with ADHD (N = 52) received mixed AMP salts extended-release (MAS XR) for a 3-week dose-optimization period, followed by a 3-week, double-blind, crossover period, during which each individual received 1 week of treatment with placebo, 1 week with MAS XR (at the individually optimized dose), and 1 week with LDX (at a dose approximately equivalent to that of MAS XR by AMP base content); the order of treatments was randomized [32]. During the double-blind treatment period, the overall level of TEAEs was low and similar among patients receiving LDX (16 %), MAS XR (18 %), and placebo (15 %) [32]. The most frequent TEAEs (>2 % with any treatment) during the double-blind treatment period for patients receiving LDX, MAS XR, and placebo were insomnia (8, 2, 2 %, respectively), decreased appetite (6, 4, 0 %), anorexia (4, 0, 0 %), upper respiratory tract infection (2, 2, 0 %), upper abdominal pain (0, 4, 2 %), and vomiting (0, 2, 4 %). The second crossover trial in children (N = 117) was a 4-week open-label period, during which the dose of LDX was individually optimized, followed by a randomized, placebo-controlled, 2-way crossover phase (1 week each of LDX or placebo) [18]. The most frequent TEAEs (≥10 %) reported for LDX-treated patients (N = 129) during the 4-week dose-optimization period were decreased appetite (47 %), insomnia (27 %), headache (17 %), irritability (16 %), upper abdominal pain (16 %), and affect lability (10 %). In two short-term, open-label trials in children (7 weeks and 4–5 weeks in duration), the profile of TEAEs was similar to those seen in other studies of LDX and alternative stimulants [34, 35]. Again, the most frequent TEAEs were related to decreased appetite and trouble sleeping.

A 5-week, placebo-controlled, crossover study of LDX in 24 university students aged 18–23 years found the most frequent TEAEs were decreased appetite and trouble sleeping [33]. A second crossover trial in adults (aged 18–55 years; N = 142) consisted of a 4-week, open-label period, during which the dose of LDX was individually optimized to 30, 50, or 70 mg daily, followed by a randomized, placebo-controlled, 2-way crossover phase (1 week each of LDX or placebo) [19]. The most common TEAEs (≥10 %) during dose optimization were decreased appetite (52 %), dry mouth (43 %), headache (28 %), insomnia (26 %), upper respiratory tract infection (14 %), irritability (12 %), and nausea (11 %). During the crossover phase, no newly emergent TEAEs were reported in 5 % or more of adults receiving LDX, and the percentage of patients with any TEAE was lower for LDX-treated individuals (32 %) than those receiving placebo (42 %).
Safety and Tolerability in Long-Term Studies

The safety and tolerability of LDX over the long term (defined for the purposes of this paper as at least 6 months) has been evaluated in extension studies to four of the randomized, parallel-group, double-blind, placebo-controlled phase III trials described above [29, 30, 36, 37]. In each long-term extension study, patients received open-label, individually dose-optimized LDX (30, 50, or 70 mg taken once daily). The open-label treatment period lasted between 26 and 52 weeks in the study in children and adolescents (study 326) and 52 weeks in the other three long-term studies in children, adolescents, and adults (studies 302, 306, and 304, respectively).

The most common TEAEs reported in the long-term extension studies are shown in Table 4. These are largely similar to those reported in the short-term trials (Table 1), and are consistent with those reported for other stimulants. The overall rate of TEAEs did not differ greatly among age groups. As with the short-term trials, the most common TEAEs for LDX-treated patients across all age groups included decreased appetite (14–33 %), headache (17–21 %), and insomnia (12–20 %). Weight loss was more common in children and adolescents (16–18 %) than in adults (6 %). Anorexia was reported in 15 % of LDX-treated children and adolescents in study 326, but occurred in 5 % or less of patients receiving LDX in the other long-term studies.
Table 4
Table 4
Treatment-emergent adverse events reported in four long-term studies (≥6 months) of lisdexamfetamine dimesylate treatment [29, 30, 36, 37]

Most TEAEs reported in the long-term studies were mild or moderate in severity [29, 30, 36, 37]. Serious TEAEs and TEAEs leading to discontinuation were reported by 1–4 % and 6–16 % of patients receiving LDX, respectively (Table 4). The serious TEAEs reported in the long-term studies in children and in adults (studies 302 and 304) were judged by the study investigator to be unrelated to LDX treatment [29, 30]. In study 326 in children and adolescents, syncope and aggression (two cases of each) were the only serious TEAEs reported in more than one patient during the open-label LDX treatment period [36]. In this study, open-label treatment was followed by randomized treatment withdrawal; no clinically relevant safety signals were associated with the abrupt discontinuation of LDX [36]. In the long-term adolescent study (study 306), of the serious TEAEs, only three episodes of syncope were considered to be related to LDX treatment [37]. In this study, any new onset of syncope was considered an important medical event requiring reporting as a serious TEAE. TEAEs that led to treatment discontinuation included insomnia, aggression, irritability, decreased appetite, and depressed mood [29, 30, 37]. The mean changes in vital signs and corrected QT interval observed during the four extension studies were modest and consistent with the profile of LDX seen in the short-term trials (Table 5).
Table 5
Table 5
Changes from baseline to endpoint in vital signs and QTcF in four long-term studies (≥6 months) of lisdexamfetamine dimesylate treatment [29, 30, 36, 37]

The safety and efficacy of LDX has also been evaluated in a long-term maintenance-of-efficacy study in adults with ADHD (study 401) [38]. This study enrolled adults aged 18–55 years who had already received at least 6 months of treatment with commercially available LDX. During the initial phase of this study, patients received open-label treatment with their established commercial dose of LDX (30, 50, or 70 mg once daily) for 3 weeks. Of 122 patients who received open-label LDX, 20 % reported a TEAE; headache (2.5 %) and upper respiratory tract infection (2.5 %) were the only TEAEs with a frequency of greater than 2 %. As with study 326, no clinically relevant safety signals were associated with the randomized withdrawal of LDX treatment following open-label treatment in study 401 [36, 38].
Post-Marketing Safety Data

Published accounts of post-marketing data describing adverse events in patients receiving LDX are limited. Spiller at al. [39] described 28 patients who reported adverse events to one of five poison centers in the USA during the first 10 months of LDX marketing. In most (86 %) of these patients, the adverse reaction occurred within the first week of therapy, with agitation (43 %), tachycardia (39 %), insomnia (29 %), dystonia (29 %), vomiting (18 %), chest pain (14 %), hallucination (11 %), and jitters (11 %) occurring in more than 10 % of the patients. In addition, there are case reports of single instances of alopecia [40] and eosinophilic hepatitis [41] in patients with ADHD treated with LDX, and of chorea [42] and serotonin-like syndrome [43] following accidental ingestion of LDX.
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Specific Safety Concerns Associated with Stimulant Use
Weight and Growth

As with other stimulants, monitoring of height and weight in pediatric patients receiving LDX is recommended [21]. Reductions in weight and in expected height gains have been reported in multiple clinical trials assessing the use of stimulants for ADHD treatment; however, the relatively short duration of most studies has limited the available data on the long-term impact of stimulants on growth. A 3-year follow-up of the National Institute of Mental Health Multimodal Treatment Study of ADHD found that stimulant-treated children were shorter by an average of 2.0 cm and lighter by 2.7 kg after 3 years compared with un-medicated children [44]. However, the reductions in growth velocity were greatest in the first year of treatment, then decreased in the second year, and were absent in the third year when compared with un-medicated children.

To evaluate the effects of LDX treatment on growth in children, data were analysed from two North American, 4- to 6-week, short-term studies (studies 301 and 201) [24, 32] and a 52-week, long-term study in children (study 302, which enrolled patients from studies 301 and 201) [29]. In this analysis, the weight, height, and body mass index (BMI) of 281 children (aged 6–13 years) were assessed for up to 15 months and compared with norms from the US Centers for Disease Control (CDC) [45]. It was noted that, at baseline, patients were significantly taller and heavier than expected based on CDC norms. The mean (standard deviation [SD]) duration of LDX treatment was 265 (149) days. Consistent with the known effects of stimulants from other long-term studies [46], compared with expected changes based in CDC norms, gains in weight, height, and BMI in children receiving LDX were statistically significantly reduced, with the greatest rate of weight decrease observed within the first 6 months of treatment [45]. Across all studies, mean weight decreased by 0.2 kg, compared with an expected increase of 3.5 kg. Mean height increased by 3.9 cm, compared with an expected increase of 4.8 cm. Among children with endpoint data obtained at or beyond 12 months, the proportion of children with a BMI below or at the fifth percentile increased from 4 % at baseline to 15 % at endpoint. Growth was most affected in the heaviest and tallest children, for those who had not previously received stimulant treatment and for those with a greater cumulative exposure to LDX [45].

In the 7-week, phase III study in children and adolescents with ADHD (study 325), mean [SD] body weight decreased in the patients receiving LDX (−2.1 [1.9] kg) and OROS-MPH (−1.3 [1.4] kg), compared with an increase (+0.7 [1.0] kg) in patients receiving placebo [25]. Of the 47 patients (LDX, n = 35; OROS-MPH, n = 12) who had a potentially clinically significant decrease in weight at endpoint (≥7 % from baseline), three patients (LDX, n = 2; OROS-MPH, n = 1) moved from healthy weight BMI categories to underweight (defined as BMI less than the 5th percentile) [25]. In the short-term, forced-dose study in adolescents (study 305), the mean (SD) weight changes from baseline at week 4 were −3.0 (2.92), −4.5 (3.91), and −5.2 (3.20) lb for the 30, 50, and 70 mg/day LDX groups, respectively, and +2.3 (2.94) lb for the placebo group (this converts to approximately −1.36 [1.33], −2.05 [1.78], and −2.36 [1.45] kg for the 30, 50, and 70 mg/day LDX groups and +1.05 [1.34] kg in the placebo group). In adolescents receiving LDX 30, 50, and 70 mg for 52 weeks (study 306), mean (SD) changes in weight from baseline to endpoint were −0.1 (3.91), −0.4 (4.80), and −1.9 (6.08) kg, respectively [37]. Of the 171 patients with a healthy weight BMI at baseline, five were categorized as underweight at endpoint; there were no underweight individuals at baseline.

The effects of LDX on weight in adults and changes over the longer term are less certain. In the 52-week study 304 in adults, the mean change in weight from baseline to endpoint was −1.8 kg [30]. An increase in BMI was observed in the one adult who was underweight at baseline. Of the 105 adults with a normal BMI (18–24 kg/m2) at baseline, one patient ended the study as underweight (BMI 17.5 kg/m2 at endpoint) and six ended the study as overweight (BMI 24.0–25.1 kg/m2).
Sleep

ADHD itself may be associated with sleep disturbances, including difficulties in initiating sleep, reduced total sleep time, and poor sleep quality [47, 48]. The mechanisms by which this occurs are not well understood, and the impacts of comorbidities and ADHD medication on sleep remain unclear [47, 48]. Clinical guidelines provide recommendations for the management of sleep disturbance [49].

Sleep impairments, including insomnia, have been recorded as TEAEs in multiple clinical trials assessing the use of stimulants to treat ADHD, indicating that stimulant therapy may be the cause of sleep problems in some patients [50]. However, in a randomized, double-blind, placebo-controlled study in children, neither once-daily OROS-MPH nor transdermal MPH appeared to cause sleep problems or to exacerbate existing sleep impairments [51]. In addition, results from a 6-week, open-label study in 24 children with ADHD indicated that OROS-MPH treatment did not impair sleep and may even improve some aspects of sleep [52]. Kooij et al. [53] reported improved sleep quality in a small sample of adults with ADHD (N = 8) following 3 weeks of open-label stimulant therapy. Similarly, another study, which included 34 adults with ADHD, found that open-label treatment with MPH had beneficial effects on sleep compared with no treatment [54]. Insomnia was reported as a TEAE in 11–19 % of patients of all ages receiving LDX in short-term, randomized, placebo-controlled, parallel-group trials, compared with 0–5 % of patients receiving placebo (Table 1). In longer-term extension studies, the proportions of patients (12–20 %) receiving LDX who reported insomnia were similar to those observed in the short-term trials (Table 4).

In study 303 in adults (N = 420), mean global scores for the self-rated Pittsburgh Sleep Quality Index (PSQI) indicated that sleep quality at baseline was generally poor but did not differ between the treatment groups (LDX 5.8, placebo 6.3, p = 0.19). By week 4, least squares mean change from baseline in PSQI global score (where a decrease indicates an improvement in sleep quality) suggested that LDX was not associated with an overall worsening of sleep quality compared with placebo (LDX −0.8, placebo –0.5, p = 0.33), but was associated with improvement in the daytime functioning component compared with placebo (p = 0.0001) [55]. A post hoc analysis of this study examining categorical changes in PSQI found that similar proportions of adults receiving placebo and LDX shifted from good sleep (PSQI ≤5) at baseline to poor sleep (PSQI >5) at endpoint (8.2 and 7.7 %, respectively), while 8.2 % of the placebo group and 20.9 % of the LDX group had better sleep at endpoint than at baseline (p = 0.03, LDX vs. placebo) [56]. Thus, while reports of sleep-related TEAEs are elevated in patients receiving LDX compared with placebo, these findings are not reflected in impaired sleep quality in adults with ADHD as measured by the PSQI [56].

Polysomnography and actigraphy parameters were examined in 24 children (aged 6–12 years) with ADHD before and after treatment with LDX in a randomized, placebo-controlled, double-blind, parallel-group study [57]. There was no statistically significant increase in latency to persistent sleep in patients treated with LDX compared with the placebo group. Furthermore, there were no significant differences between LDX and placebo in actigraphy and secondary polysomnography measures. However, the number of awakenings after sleep onset significantly decreased from 7.9 at baseline to 3.3 at week 7 in the LDX treatment group (p < 0.0001 compared with baseline). However, owing to the small sample size and exploratory nature of this pilot study, these results should be interpreted with caution. Overall, the impact of stimulants on sleep in patients with ADHD is unclear. The heterogeneity of observations across studies may reflect differences in the class of drug, formulation, and dose-scheduling protocols [49]. Intuitively, a stimulant with a duration of action lasting into the evening following a single morning dose might be expected to be associated with sleep-related TEAEs yet, paradoxically, patients receiving shorter-acting formulations may experience sleep disturbances due to a rebound effect in the evening after their medication wears off [49]. Abuse Potential Like other stimulants, LDX is a controlled substance with the potential for non-medical use (NMU) and diversion [21]. Several pharmacokinetic and physicochemical characteristics of LDX may lower the potential for abuse, misuse, or diversion compared with immediate-release stimulant formulations. First, in common with all long-acting stimulants, once-daily dosing makes parental supervision easier to enforce [5]. Second, the maximum plasma concentration of d-AMP is reached approximately 3.5 h after a single dose of LDX in children with ADHD, with an elimination half-life ranging from 8.61 to 8.90 h [16]. The ‘high’ associated with stimulants is dependent on a rapid rise in stimulant concentration and the resultant increase in monoamine receptor occupancy [58]. Accordingly, the absence of an early sharp rise and spike in systemic d-AMP concentrations following LDX administration may result in a lower abuse potential compared with immediate-release AMP formulations [59]. Third, the requirement for LDX to be converted to d-AMP via rate-limited hydrolysis in the blood means that opening LDX capsules, or dissolving the contents in water, will not yield the active ingredient d-AMP for direct administration [59]. Finally, a randomized, crossover study in healthy men suggested that switching between oral and intranasal routes of administration of LDX does not markedly modify d-AMP plasma concentration–time profiles [60]. Drug-liking scores for LDX were assessed in two phase I studies in adult volunteers with a history of stimulant abuse. These studies found that drug-liking scores for oral (100 mg) and intravenous (25 and 50 mg) LDX were not significantly different from placebo and were lower than those for equivalent doses of immediate-release d-AMP [59, 61]. The lower drug-liking of LDX compared with d-AMP at equivalent doses are presumably due to the delayed pharmacodynamic properties of the former that result from the prodrug nature. At the supra-therapeutic oral dose of 150 mg, the drug-liking score for LDX was similar to that of 40 mg d-AMP, despite a 50 % greater AMP free-base content in the former compared with the latter, and drug-disliking scores were higher [59]. While these results are suggestive of a lower potential for the abuse of LDX than d-AMP, it should be noted that the studies enrolled small numbers of individuals who received LDX for short periods of time under controlled conditions. Large-scale, post-marketing data relevant to the abuse-liability of LDX are beginning to emerge. An internet survey of 10,000 US adults (aged 18–49 years) reported lifetime NMU of pain medications, sedatives/tranquilizers, sleep medications, and prescription stimulants to be 24.6, 15.6, 9.9, and 8.1 %, respectively. Within prescription stimulants, product-specific rates of NMU (per 100,000 prescriptions dispensed) were generally low but highest for immediate-release formulations (Ritalin®, 1.62; Adderall®, 1.61) compared with longer-acting preparations (Adderall XR® 0.62, Concerta® 0.19, LDX 0.13) [62]. The most commonly reported motivation for stimulant NMU in this study were ‘increasing alertness’ (33–61 %) and ‘enhancing academic or work performance’ (39–57 %) rather than ‘getting high’ (20–30 %) [62]. A second evaluation of the NMU of prescription ADHD stimulants among adults was based on 147,816 assessments from the National Addictions Vigilance Intervention and Prevention Program (NAVIPPRO) system. NMU, over the previous 30 days, of prescription stimulants (1.29 %) was lower than for opioids (19.79 %) and sedatives (10.62 %). Again, NMU of stimulant products was low: Ritalin®, 0.16; Adderall® 0.62; Adderall XR®, 0.42; Concerta®, 0.08; LDX 0.12) [63]. A cross-sectional, population-based US survey, which included 443,041 respondents from the 2002–2009 National Survey on Drug Use and Health, found that lifetime NMU of prescription ADHD stimulants was reported by 3.4 % of respondents aged 12 years or older, most of whom had already been engaged in the abuse of an illicit drug or NMU of another prescription drug [64]. In addition, data from the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS®) System, a US national surveillance system that monitors the abuse, misuse, and diversion of prescription controlled substances, indicated that RADARS System Poison Center call rates and RADARS System Drug Diversion rates for prescription stimulants were low and that rates for extended-release AMP formulations, including LDX, were similar to those for extended-release MPH (from third quarter of 2007 to second quarter of 2011) [65]. Cardiovascular Safety Case reports of sudden death in stimulant-treated patients, combined with the sympathomimetic properties of this class of drug, led European and North American treatment guidelines to recommend that clinicians be aware of any cardiovascular risks that may affect a patient’s suitability for ADHD medication [1, 2, 6, 66]. Thus, prescribing information for LDX warns of the risk of serious cardiovascular reactions, including sudden death, and recommends that its use is avoided in patients with cardiac abnormalities, cardiomyopathy, serious heart arrhythmia, or coronary artery disease [21]. Furthermore, the checking of fingers and toes for circulation problems (peripheral vasculopathy, including Raynaud’s phenomenon) has recently become a requirement for patients receiving stimulants, including LDX, for the treatment of ADHD [21]. However, most large-scale epidemiological studies and randomized, controlled trials have failed to substantiate concerns of elevated cardiovascular risk of ADHD medications [67–69]. Of a series of five retrospective, administrative claims-based US studies in children and adolescents, the two smallest studies did report a slightly increased risk of emergency department visits attributed to cardiac symptoms such as tachycardia or palpitations, but the three largest studies, each comprising more than a million patients, found no association between stimulants and composite endpoints of sudden cardiac death, myocardial infarction, stroke, and ventricular arrhythmia [68]. Similarly, a retrospective study that examined the UK General Practice Research Database found no increased risk of sudden death associated with ADHD medications (stimulants or ATX) in a population of 18,637 aged 2–21 years [70]. Although background rates of serious cardiovascular events in children and adolescents are small [68], evidence of an increased risk of serious cardiac events in adult patients receiving ADHD medications is also limited. A retrospective US study of healthcare records of 443,198 adults aged 25–64 years (150,359 of whom received ADHD medications) found no evidence of sudden cardiac death, myocardial infarction, or stroke associated with the use of ADHD medication compared with no use [71]. Finally, a recent retrospective study of Medicaid and commercial US databases of 43,999 adult (≥18 years of age) new MPH users and 175,955 matched non-users found a small increased risk of sudden death or ventricular arrhythmia (but not stroke, myocardial infarction, or combined stroke/myocardial infarction) among MPH users, although the lack of a dose-response effect argued against a causal relationship [72]. Cardiovascular-related serious TEAEs and discontinuations, and ECG abnormalities, were rare in clinical trials of LDX. In short-term double-blind, randomized, controlled, phase III trials in patients with ADHD of all ages, LDX was associated with modest increases in systolic and diastolic BP and pulse rate [23–27]. Outlier data reported for study 317 in children and adolescents indicated that 15.0 % of patients receiving LDX had a pulse rate ≥100 bpm compared with 24.2 % of patients receiving ATX at some point during the study. In this study, similar proportions of children receiving LDX and ATX experienced systolic BP (SBP) ≥120 mmHg (LDX 12.8 %, ATX 11.2 %) or diastolic BP (DBP) >80 mmHg (LDX 11.7 %, ATX 13.3 %), and similar proportions of adolescents experienced SBP ≥130 mmHg (LDX 6.1 %, ATX 8.8 %) or DBP >80 mmHg (LDX 21.2 %, ATX 17.6 %). There were no cases of QTcF interval ≥450 ms [27]. In study 305 in adolescents, 3.0 % of patients receiving LDX had a heart rate ≥100 bpm at endpoint compared with none receiving placebo. No participants had a QTcF interval of ≥480 ms [26]. Post hoc analyses of cardiovascular parameters in adults (study 303) found that the proportions of patients who experienced a pulse rate of ≥100 bpm during treatment with LDX ranged from 3.3 % for the 70-mg dose to 8.5 % for the 50-mg dose; no patients in the placebo group exceeded this threshold [31]. There were no clinically meaningful ECG abnormalities [23]. Modest increases in cardiovascular vital signs were also reported during the crossover phase of a placebo-controlled classroom study in children (aged 6–12) with ADHD in both LDX and placebo groups [18]. Maximum mean (SD) increases in pulse rate, SBP, and DBP (9.9 [9.8] bpm, 4.2 [9.2] mmHg, and 4.7 (8.5) mmHg, respectively) were all observed in the LDX 70-mg group. Finally, a small (N = 28), 4- to 5-week, single-blind, modified laboratory school study in children (aged 6–12 years) with ADHD reported one case each of tachycardia, BP >95th percentile of normal range (both occurred once only), and a prolongation of QTc (461 ms, which resolved at medication discontinuation and did not reappear at the resumption of treatment) in patients receiving LDX [73].

In the short-term, randomized, double-blind trial in children (study 301), ECG voltage criteria for ventricular hypertrophy led to discontinuation of at least 1 % of patients receiving LDX [21], although subsequent analysis of these data suggested that minor variations in ECG interpretation contributed to these discontinuations (data on file). To assess the impact of LDX treatment on cardiovascular and cardiopulmonary structure and function using comprehensive provocative physiological testing, a prospective open-label study was conducted in 15 adults with ADHD [74]. Participants were treated with LDX for up to 6 months and underwent transthoracic echocardiography and cardiopulmonary exercise testing. This study found no clinically meaningful changes in cardiac structure and function, or in metabolic and ventilatory variables at maximum exertion. However, the authors acknowledged that, while their results are generally reassuring, these findings were limited by the small sample size and uncontrolled nature of the study design.
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Caveats of Reported Lisdexamfetamine Dimesylate (LDX) Safety Outcomes

The interpretation of safety and tolerability data from the LDX clinical trial program requires that several limitations be considered. First, the relatively small number of patients enrolled in clinical trials of relatively short duration means that rare TEAEs, or TEAEs that emerge only after extended treatment, are unlikely to be detected. Second, it is important to note that individuals with comorbid psychiatric disorders, extremes of weight, or major neurological and cardiovascular conditions were excluded from the clinical trials, and all patients were in generally good health. Third, is the tendency for long-term studies in particular to self-select for responders. Thus, it is unlikely that these phase III clinical trials of LDX reflect the full spectrum of patients seen in clinical practice. Finally, it should be acknowledged that all of the clinical trials described were sponsored by the manufacturer of LDX.

Post-marketing surveillance can provide additional information regarding drug safety in clinical practice and TEAEs reported in patients treated with LDX during the post-marketing period [21]. However, these data rely on voluntary reporting of TEAEs from a population of uncertain size, making it difficult to estimate the frequency of events or to establish a causal relationship to drug exposure reliably [21]. The EU-based, Attention Deficit Drugs Use Chronic Effects (ADDUCE) Consortium has been established, at the request of the European Medicines Agency and with European Union FP7 funding, in response to the lack of knowledge regarding the long-term effects of stimulants [75]. Initially focusing on MPH treatment, the ADDUCE project plans to perform a series of pharmacovigilance investigations into the long-term effects of stimulants on growth, the neurological system, psychiatric states, and the cardiovascular system, and it is hoped that new research tools developed during this process can then be applied to other ADHD medications, including LDX. With the exception of LDX misuse mentioned earlier, published large-scale, post-marketing data on LDX are currently limited. However, a company-sponsored phase IV, open-label study (study 404) is underway and will provide information regarding the safety profile of LDX in children and adolescents with ADHD over a 2-year treatment period.
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slutsatser

Results from clinical trials of LDX indicate that this once-daily, long-acting prodrug stimulant has a safety and tolerability profile similar to that of other stimulants. The TEAEs reported most commonly in children, adolescents, and adults include decreased appetite and insomnia. Most TEAEs are mild to moderate in severity. Due to the sympathomimetic effects of LDX, small mean increases in blood pressure and pulse rate can occur. These changes alone would not be expected to have short-term consequences, but all patients receiving LDX should be monitored for larger changes in blood pressure and pulse rate, and LDX should not be used in patients with serious cardiac problems. As a result of its prodrug formulation, there is low intra- and inter-patient variability in the systemic exposure to d-AMP, which may help facilitate LDX dose optimization. The prodrug formulation of LDX may also lead to reduced abuse potential of LDX compared with immediate-release d-AMP. Overall, the choice of medication for patients with ADHD should be based on the benefit–risk ratio for each individual.
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erkännanden

The authors thank Drs Elizabeth Gandhi and Eric Southam of Oxford PharmaGenesis™ who provided editorial support funded by Shire, including collating the comments of the authors and editing the manuscript for submission.
Disclosures

LDX is manufactured and marketed by Shire. B Caballero, S Sorooshian, and R Civil are employees of Shire and own stock/stock options. DR Coghill has received compensation for serving as a consultant or speaker; or has, or the institutions he works for have, received research support or royalties from the following companies or organizations: Flynn Pharma, Janssen-Cilag, Lilly, Medice, Novartis, Otsuka, Oxford University Press, Pfizer, Schering-Plough, Shire, UCB, Vifor Pharma.
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Referenser
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39. Spiller HA, Griffith JR, Anderson DL, Weber JA, Aleguas A. Poison centers detect an unexpectedly frequent number of adverse drug reactions to lisdexamfetamine. Ann Pharmacother. 2008;42(7):1142–1143. doi: 10.1345/aph.1L240. [PubMed] [Cross Ref]
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Articles from Springer Open Choice are provided here courtesy of Springer

Lisdexamfetamine Dimesylate
The First Prodrug Stimulant
David W. Goodman, MDcorresponding author
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This article has been cited by other articles in PMC.
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abstrakt

Attention deficit hyperactivity disorder (ADHD) is one of the most common neurobehavioral disorders affecting children. The symptoms often persist into adolescence and adulthood, causing significant impairments. ADHD often remains undiagnosed and untreated, and because of its potential long-term impact, recognition, diagnosis, and management in children have become increasingly important. Education about ADHD and the available therapy options is important for both the patient and the caregiver to achieve more effective treatment. Efficacy and safety data on stimulant medications have provided evidence for their effectiveness in treating ADHD. Although they remain the first-line treatment, the need for multiple daily dosing and concerns about the general risk profile of stimulants have led to the development of new agents, including once-daily formulations that provide prolonged duration of action. However, pharmacokinetic variability of these formulations can result in inconsistent effects in some patients. The use of prodrug technology and the development of the only prodrug stimulant, lisdexamfetamine dimesylate (LDX), provide a promising treatment option for ADHD with an improved overdose potential risk profile when compared to d-amphetamine. This review of LDX, which presents the efficacy, safety, and pharmacokinetic profile of this new class of stimulant, is designed to help the physician better understand the clinical use of this agent in treating ADHD.
Keywords: ADHD, stimulant medications, prodrugs, lisdexamfetamine dimesylate, Vyvanse
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Inledning

Attention deficit hyperactivity disorder (ADHD) is one of the most common behavioral disorders in childhood, estimated to occur worldwide in as many as eight percent to 12 percent of children.1 Childhood ADHD persists into adolescence and adulthood in an estimated 10 percent to 70 percent of cases,2–4 with impairing symptoms experienced by at least 50 percent of these patients.1 A US epidemiologic adult ADHD study reported a prevalence of 4.4 percent, yet only a small fraction of adults with ADHD (10.9%) had received treatment prior to the survey.5

Stimulants have the most evidence for efficacy and safety for the treatment of ADHD and remain the first-line therapy for ADHD.6 Concerns about the general risk profile of stimulant medications in clinical practice are common, including the association between ADHD and substance use disorder.7 Tampering, including mechanical manipulation, of some formulations has allowed misuse through administration via intended or non-intended routes and has led to the need for the development of new agents,8 including nonstimulants, developed as nonabusable alternatives for ADHD.

Since 2000, once-daily, modified-release stimulant formulations that provide prolonged delivery have been developed for the treatment of ADHD.9 While it is not known if this pharmacokinetic variability contributes to therapeutic duration variability, formulations with less pharmacokinetic variability may provide more consistent clinical results.10 More recently, development of long-acting formulations has included a prodrug stimulant representing a new class of agents for the treatment of ADHD that has less pharmacokinetic variability and the potential to produce more consistent clinical effects and less abuse potential.
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Prodrugs: a New Class of Stimulants for the Treatment of ADHD

The concept of prodrugs as a useful formulation was proposed as early as 1958 by Adrien Albert, who described the alteration of the physiochemical properties of drugs to render them pharmacologically inactive until metabolized in the body to the active drug moiety.11 By definition, a prodrug is a compound that undergoes biotransformation before exhibiting its therapeutic effect.12,13 Some therapeutically effective prodrugs include the oral fluoropyrimidine chemotherapy agents, capecitabine and uracil, prodrugs of 5-fluorouracil, and the thienopyridine antiplatelet agents, ticlopidine and clopidogrel.

Lisdexamfetamine dimesylate (LDX, Vyvanse™; Shire US Inc.) is the only prodrug stimulant and is indicated for the treatment of ADHD in children aged 6 to 12 years. LDX is a therapeutically inactive molecule; after oral ingestion, it is converted to l-lysine, a naturally occurring essential amino acid, and active d-amphetamine, which is responsible for the drug’s activity. LDX is unlike other long-acting stimulants in that it is not an encapsulated matrix or a bead formulation, but instead has extended-release characteristics because it is a prodrug.9 LDX was developed with the goal of providing once-daily treatment with an extended duration of effect that is consistent throughout the day, with a reduced potential for abuse, overdose toxicity, and drug tampering.
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Solubility and Pharmacokinetic Studies of Lisdexamfetamine Dimesylate

In-vitro study. The pH solubility profile of LDX in saturated buffered aqueous solutions (pH 1–13) was determined by a high-pressure liquid chromatography assay that was specific for LDX. Within a physiologically relevant pH range (pH 1–8), the solubility profile of LDX was not affected by the pH of the solution, and increasing the pH from 8 to 13 resulted only in modest reductions in LDX solubility.14 The results suggest that the conversion of LDX to d-amphetamine should not be affected by gastrointestinal pH. Therefore, alkalinizing agents, such as sodium bicarbonate or other antacids, should not affect the absorption of LDX. Because LDX is a prodrug that is rapidly absorbed from the gastrointestinal tract and converted to d-amphetamine, it is not a controlled-release delivery vehicle and is unlikely to be affected by alterations in normal gastrointestinal transit times.

Phase I study. The pharmacokinetic profile of the LDX formulation was determined in a phase I, open-label, randomized, single-dose, three-treatment, three-period, crossover study.14,15 This comprised three 1-week study periods with 7-day washout between doses. Eighteen healthy volunteers (9 males, 9 females) aged 18 to 55 years received a single LDX dose of 70mg under three dose conditions: (1) fasting and with capsule only; (2) solution containing capsule contents; and (3) intact capsule after a high-fat meal. The analysis showed that when LDX was administered in solution or as an intact capsule with or without food, d-amphetamine systemic exposure bioavailability was equivalent for all dosing conditions as evidenced by AUC and Cmax values. However, significant differences in tmax values (mean hours±SD) were seen between the fasted (3.8 ± 1.0) and fed (4.7 ± 1.1) conditions (p<0.001). Overall, these results demonstrated that LDX may be taken with or without food or dissolved in water and immediately consumed, without affecting the overall extent of absorption. Phase II study. The inter-subject (patient to patient) pharmacokinetic variability of d-amphetamine after oral administration of LDX and mixed amphetamine salts (MAS XR; Adderall XR®) was determined in a phase II study.16 Previous pharmacokinetic studies of MAS XR in healthy volunteers have shown considerable inter-subject variability in serum plasma d-amphetamine levels (Cmax) over time.10 This randomized, multicenter, double-blind, three-treatment, three-period, crossover study included children aged 6 to 12 years with a primary diagnosis of ADHD as defined by Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria.17 As a secondary trial objective, pharmacokinetic data were reported at the last visit for the largest patient cohort, eight patients who received 70mg/day of LDX and nine patients who received 30mg/day of MAS XR (equivalent d-amphetamine base doses) for one week. Levels of d-amphetamine reached median tmax in 4.5 hours (mean 5.1, range 4.5–6) for LDX and 6.0 hours (mean 6.6, range 3–12) for MAS XR (Table 1).16 Corresponding percent coefficients of variation were 15.3 percent and 52.8 percent, respectively, meaning that the tmax is 3.5 times less variable with LDX than MAS XR. Mean (± SD) maximum plasma concentrations (Cmax) were 155±31.4ng/mL for LDX and 119±52.5ng/mL for MAS XR. Corresponding coefficients of variation were 20.3 percent and 44.0 percent, respectively. Release of d-amphetamine was more predictable after oral administration of 70mg of LDX than 30mg of MAS XR as measured by tmax and Cmax. Overall, LDX demonstrated low inter-subject variability of pharmacokinetic measures with consistent exposure to d-amphetamine.16 Tabell 1 Tabell 1 Pharmacokinetics of d-amphetamine after oral administration of 70mg/day of LDX or 30mg of MAS XR Gå till: Efficacy Studies With Lisdexamfetamine Dimesylate The efficacy and safety of LDX for the treatment of ADHD were established on the basis of results from two controlled clinical trials in children aged 6 to 12 years who met DSM-IV criteria for ADHD.18–20 Phase II study. Biederman and Boellner, et al., recently conducted a multicenter, double-blind, placebo-controlled, crossover-design, analog-classroom study in 52 children with ADHD aged 6 to 12 years (mean, 9.1±1.7 years).18,20 After three weeks of open-label dose adjustment and optimization with 10, 20, or 30mg/day of MAS XR, subjects were randomly assigned in a crossover design to treatment with the same doses of MAS XR; equivalent LDX doses of 30, 50, and 70mg/day, respectively; or placebo once daily for one week. Efficacy was assessed by means of the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Deportment Rating Scale, the Permanent Product Measure of Performance (PERMP) scale, and the Clinical Global Impressions-Improvement (CGI-I) scale. For each measure of efficacy (SKAMP, PERMP, and CGI-I scales), similar improvements were seen in children receiving LDX and MAS XR at each time point over 12 hours, and each treatment was significantly better at all doses than placebo (p<0.0001). On the CGI-I, ratings of very much improved or much improved were seen in 74 percent of subjects who received LDX and 72 percent of those who received MAS XR, compared with 18 percent of subjects receiving placebo (Figure 1). Thirty-two percent of subjects who received LDX were rated very much improved compared with 16 percent of subjects who received MAS XR and two percent of subjects who received placebo. Adverse events (AEs) were reported by 29 of the 52 subjects during the study. The most common AEs reported with MAS XR during the open-label, dose-titration phase were headache (15%), decreased appetite (14%), and insomnia (10%). During the double-blind phase, 16 percent of LDX-treated subjects, 18 percent of MAS XR-treated subjects, and 15 percent of placebo-treated subjects reported AEs. AEs that occurred during the double-blind phase with an incidence rate of ≤2 percent were insomnia (8%), decreased appetite (6%), and anorexia (4%) in LDX-treated subjects; decreased appetite (4%), upper abdominal pain (4%), vomiting (2%), and insomnia (2%) in MAS XR-treated subjects; and vomiting (4%), insomnia (2%), and upper abdominal pain (2%) in placebo-treated subjects. No serious AEs were reported. Figures 1 Figures 1 Clinical Global Impressions Scale - Mean improvement at assessment from baseline for intent-to-treat population who received placebo, LDX, or MAS XR.18,20 Phase III study. Biederman, et al., also conducted a double-blind, multicenter, placebo-controlled, parallel-group study in 290 children (201 boys and 89 girls) aged 6 to 12 years (mean, 9±1.8 years) with a primary diagnosis of ADHD.19 The children were randomly assigned to fixed-dose treatments consisting of oral doses of 30, 50, or 70mg/day of LDX or placebo once daily each morning for four weeks. A forced-dose design was employed for LDX treatments to assess the efficacy and tolerability of each individual dose as follows: 30mg for four weeks, 50mg (30mg/day for Week 1, with forced-dose escalation to 50mg/day for Weeks 2–4), or 70mg (30mg/day for Week 1, with forced-dose escalation to 50mg/day for Week 2 and 70mg/day for Weeks 3 and 4). Efficacy was assessed using the parent- and investigator-completed ADHD Rating Scale (ADHD-RS), the CGI-I, and the Conners Parent Rating Scale (CPRS). Of the 290 randomized patients, 230 completed the study (56 patients received LDX 30mg, 60 patients received LDX 50mg, 60 patients received LDX 70mg, and 54 patients received placebo). Significantly greater improvements in ADHD-RS total scores (mean change from baseline to endpoint) were seen with each of the three LDX doses compared with placebo (p<0.001 for all comparisons). Based on ADHD-RS scores at treatment endpoint, the effect sizes were 1.21, 1.34, and 1.60 in the 30-, 50-, and 70-mg groups, respectively, determined by the corresponding between-group differences. Throughout the study, assessment of symptomatic behaviors of ADHD using the CPRS in the morning (~10 AM), afternoon (~2 PM), and evening (~6 PM) showed significantly greater improvements (p<0.01) in symptom control throughout the day in each LDX dose group than in patients who received placebo. CGI-I scores were significantly improved (p<0.0001) with all three doses of LDX compared with placebo; ratings of very much improved or much improved were seen in ≤70 percent of patients in the LDX treatment groups compared with 18 percent of patients who received placebo. Overall, AEs in patients who received LDX were typical of amphetamine products.19 The most frequently reported AEs among patients receiving LDX compared with placebo were decreased appetite (39% vs. 4%), insomnia (19% vs. 3%), upper abdominal pain (12% vs. 6%), headache (12% vs. 10%), irritability (10% vs. 0%), vomiting (9% vs. 4%), weight decrease (9% vs. 1%), and nausea (6% vs. 3%). Most AEs were mild to moderate and occurred in the first week of treatment. Treatment with LDX was not associated with statistically significant changes in laboratory values, mean electrocardiogram (ECG) values (including corrected QT intervals), and systolic or diastolic blood pressure measures.21 There was a statistically significant change in pulse relative to placebo at endpoint, with each active treatment group showing an increase from baseline. The least-squares mean differences versus placebo in pulse rate from baseline to endpoint were 0.3±1.2 bpm for the LDX 30mg group (baseline pulse 82.2 bpm), 2.0±1.2 bpm for the 50mg group (baseline pulse 81.7 bpm), and 4.1±1.2 bpm for the 70mg group (baseline pulse 82.8 bpm) (p=0.0224, ANCOVA). No statistically significant changes from baseline were seen for any individual treatment week. Observed changes were not clinically meaningful and were consistent with results seen with other stimulant agents. Long-term efficacy and safety of LDX-phase III study. A 12-month, open-label, single-arm study was conducted to determine the long-term efficacy and safety of LDX in children.22 The intent-to-treat population consisted of 189 boys and 83 girls aged 6 to 12 years (mean, 9.2 years) with DSM-IV diagnosis for ADHD. Subjects were previously enrolled in a double-blind clinical study and may or may not have received prior treatment with LDX, except for one subject who was newly enrolled. After a one-week washout period, all subjects were started on 30mg/day of LDX and either maintained on this dose or titrated by the investigator to a dose of 50 or 70mg/day over a four-week period, based on effectiveness and tolerability. Treatment was maintained for up to 11 more months during which the doses could be changed for optimal effectiveness and tolerability; however, most of the dose changes occurred early in the study, suggesting that tolerance to medication did not occur. Efficacy was assessed using the ADHD-RS scores at endpoint and from baseline over the course of treatment, and the CGI-I scale.22 At endpoint (last observation), there was significant improvement (>60%, p<0.0001) in ADHD-RS total scores compared with baseline. Beginning at week 4, reductions in ADHD-RS total scores occurred and were seen throughout the 12-month treatment period. Using a clinician-completed rating scale (CGI), more than 80 percent of the patients were rated as much improved or very much improved by study endpoint. Additionally, more than 95 percent of those who completed 12 months of treatment were improved. LDX was generally well tolerated, with most of the treatment-related AEs occurring during the first eight weeks of treatment. AEs reported in 10 percent or more of the patients included decreased appetite, weight decrease, headache, insomnia, upper abdominal pain, upper respiratory infection, nasopharyngitis, and irritability. During the second eight weeks of treatment, only decreased appetite and weight decrease occurred in more than five percent of subjects. No statistically or clinically significant changes in ECG values or blood pressure were seen over the study period.23 The mean changes from baseline were 0.3 to 3.5 bpm for pulse; -1.8 to 1.0mmHg for systolic blood pressure; and -1.0 to 0.7mmHg for diastolic blood pressure. The mean increases from baseline in heart rate ranged from 1.8 to 5.2 bpm. Mean changes in QT/QTc intervals ranged from -4.7 to -1.8msec for QT, -0.4 to 2.2msec for QTc-F, and 1.1 to 6.4 msec for QTc-B. Twenty five (9%) of the 272 LDX-treated subjects discontinued treatment because of AEs, including three for decreased appetite, three for irritability, three for aggression, two for anxiety, and two for decreased weight. There were no discontinuations related to ECG findings. Gå till: Abuse Liability Data LDX is the only product for the treatment of ADHD that includes abuse liability data in the product label. Support for the reduced abuse potential of LDX relative to immediate-release d-amphetamine has been shown in two abuse liability studies in human subjects.24,25 The abuse potential of oral LDX and d-amphetamine was compared in 38 adult non-ADHD subjects who had a history of stimulant abuse.24 In the double-blind, placebo-controlled, crossover study, oral doses of 50mg, 100mg (equivalent to 40mg of d-amphetamine), and 150mg of LDX and 40mg of d-amphetamine sulfate were administered. For the primary measure of subjective responses on a scale of the drug-liking effects, the Drug Rating Questionnaire-Subject (DRQS) Liking Scale, the maximum post-dose change in score from baseline was significantly greater in the subjects who received d-amphetamine 40mg than the equivalent 100-mg dose of LDX (p<0.05) when compared to placebo. Mean drug-liking scores peaked between 1.5 and 2 hours post-dose in subjects who received d-amphetamine and between 3 and 4 hours post-dose in subjects who received LDX, in keeping with the slower rise in LDX blood level. At a higher dose of LDX (150mg; equivalent to 1.5 times the dose of d-amphetamine used in this study), the maximum drug-liking score was similar to that after 40mg of d-amphetamine; however, the peak effect of LDX was two hours later than that of d-amphetamine, reflecting a slow ascent in serum level. In the second double-blind crossover study, equivalent intravenous doses of 50mg of LDX and 20mg of d-amphetamine were administered over a two-minute period at 48-hour intervals to nine adult non-ADHD subjects who had a history of drug abuse.25 Intravenous LDX at doses of 50mg did not produce significantly different liking scores as measured by the DRQS Liking Scale compared with placebo (p=0.29). In contrast, equivalent doses of 20mg of intravenous d-amphetamine did have significantly more liking effects than placebo (p=0.01). Mean peak behavioral and subjective effects were observed at 15 minutes post-dosing for d-amphetamine and between 1 and 3 hours for LDX. Gå till: Slutsats Recognition, diagnosis, and management of ADHD in children have become increasingly important in the primary care setting. Stimulants remain the first-line treatment for ADHD, but the need for multiple daily dosing can be problematic for some patients when using short-acting stimulants. Concerns about the general risk profile of stimulant medications have led to the need for the development of new agents, including once-daily stimulant formulations that provide a prolonged duration of action and may have a reduced potential for risk of abuse. Although long-acting formulations have been shown to be effective in treating ADHD, pharmacokinetic variability can theoretically result in inconsistent duration of action across patients. The recent development and approval of LDX, the only prodrug stimulant, represents a new class of agents for the treatment of ADHD. Clinical evidence supports the effectiveness of LDX in the treatment of children with ADHD, while exhibiting reduced pharmacokinetic variability in maximum concentration and time to maximum concentration, and a tolerability profile similar to that of other long-acting stimulants. LDX has been shown to provide significant symptom control throughout the day for children with ADHD. In human abuse liability studies, LDX produced lower subjective responses on a test of drug-liking effects than dose-equivalent immediate-release d-amphetamine. In human abuse liability studies with oral and intravenous administration, LDX produced lower subjective responses on a test of drug-liking effects in adult substance abusers compared to dose-equivalent immediate-release d-amphetamine.24,25 The reduced drug-likability is a unique attribute of LDX relative to other stimulant preparations and is cited in the prescribing information.26 Gå till: erkännanden I thank the staff of Excerpta Medica, Bridgewater, New Jersey, for their assistance in the preparation of this manuscript. Gå till: Referenser 1. Biederman J, Faraone SV.Attention-deficit hyperactivity disorder. Lancet.2005;366:237–48.[PubMed] 2. Spencer TJ, Adler LA, McGough JJ, et al. and The Adult ADHD Research Group. Efficacy and safety of dexmethylphenidate extended-release capsules in adults with attention-deficit/hyperactivity disorder. Biol Psychiatry. 2007;61:1380–7. [PubMed] 3. McGough JJ, Barkley RA. Diagnostic controversies in adult attention deficit hyperactivity disorder. Am J Psychiatry. 2004;161:1948–56. [PubMed] 4. Faraone SV, Biederman J, Mick E. The age-dependent decline of attention deficit hyperactivity disorder: A meta-analysis of follow-up studies. Psychol Med. 2006;36:159–65. [PubMed] 5. Kessler RC, Adler L, Barkley R, et al. The prevalence and correlates of adult ADHD in the United States: Results from the National Comorbidity Survey Replication. Am J Psychiatry. 2006;163:716–23. [PMC free article] [PubMed] 6. Pliszka SR, Crismon ML, Hughes CW, et al. The Texas Consensus Conference Panel on Pharmacotherapy of Childhood Attention-Deficit/Hyperactivity Disorder. The Texas Children’s Medication Algorithm Project: Revision of the algorithm for pharmacotherapy of attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2006;45:642–57. [PubMed] 7. Wilens TE. Impact of ADHD and its treatment on substance abuse in adults. J Clin Psychiatry. 2004;65(3):38–45. [PubMed] 8. Cone EJ. Ephemeral profiles of prescription drug and formulation tampering: Evolving pseudoscience on the Internet. Drug Alcohol Depend. 2006;83S:S31–9. [PubMed] 9. Markowitz JS, Straughn AB, Patrick KS. Advances in the pharmacotherapy of attention-deficit-hyperactivity disorder: Focus on methylphenidate formulations. Pharmacotherapy. 2003;23:1281–99. [PubMed] 10. McGough JJ, Biederman J, Greenhill LL, et al. Pharmacokinetics of SLI381 (ADDERALL XR), an extended-release formulation of Adderall. J Am Acad Child Adolesc Psychiatry. 2003;42:684–91. [PubMed] 11. Albert A. Chemical aspects of selective toxicity. Nature. 1958;182:421–3. [PubMed] 12. Stanczak A, Ferra A. Prodrugs and soft drugs. Pharmacol Rep. 2006;58:599–613. [PubMed] 13. Schuster CR. History and current perspectives on the use of drug formulations to decrease the abuse of prescription drugs. Drug Alcohol Depend. 2006;83S:S8–14. [PubMed] 14. Shojaei A, Ermer JC, Krishnan S. Lisdexamfetamine dimesylate as a treatment for ADHD: Dosage formulation and pH effects. 2007. May 19, Poster presented at the American Psychiatric Association Annual Meeting. San Diego. 15. Arora M, Krishnan S. Bioavailability of lisdexamfetamine dimesylate in healthy volunteers when administered with or without food. 2006. Oct 6, Poster presented at the Institute on Psychiatric Services. New York. 16. Ermer JC, Shojaei AH, Biederman J, Krishnan S. Improved interpatient pharmacokinetic variability of lisdexamfetamine dimesylate compared with mixed amphetamine salts extended release in children aged 6 to 12 years with attention-deficit/hyperactivity disorder. 2007. May 19, Poster presented at the American Psychiatric Association Annual Meeting. San Diego. 17. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fourth Edition. Washington (DC): American Psychiatric Press Inc.; 2000. Text Revision. 18. Biederman J, Boellner SW, Childress A, et al. Lisdexamfetamine dimesylate and mixed amphetamine salts extended-release in children with ADHD: A double-blind, placebo-controlled, crossover analog classroom study. Biol Psychiatry. 2007 In press. [PubMed] 19. Biederman J, Krishnan S, Zhang Y, et al. Efficacy and tolerability of lisdexamfetamine dimesylate (NRP-104) in children with attention-deficit/hyperactivity disorder: A phase III, multicenter, randomized, double-blind, forced-dose, parallel-group study. Clin Ther. 2007;29:450–63. [PubMed] 20. Boellner SW, Childress AC, Krishnan S, et al. ADHD symptom improvement in children treated with lisdexamfetamine dimesylate: CGI. 2007. Apr 15, Poster presented at the 2007 College of Psychiatric and Neurologic Pharmacists. Colorado Springs. 21. Wayne PA. Shire Development, Inc. Data on File. Study Clinical Report NRP104.301, collected 11-02-2005. 22. Findling RL, Childress AC, Krishnan S, McGough JJ. Long-term efficacy and safety of lisdexamfetamine in school-age children with attention-deficit/hyperactivity disorder. 2007. May 19, Poster presented at the American Psychiatric Association Annual Meeting. San Diego. 23. Findling RL, Lopez FA, Childress AC, et al. Long-term safety and tolerability of lisdexamfetamine dimesylate in children aged 6 to 12 years with attention-deficit/hyperactivity disorder. 2007. Jun 11, Poster presented at the New Clinical Drug Evaluation Unit Annual Meeting. Boca Raton. 24. Jasinski D, Krishnan S. A double-blind, randomized, placebo- and active-controlled, 6-period crossover study to evaluate the likability, safety, and abuse potential of lisdexamfetamine dimesylate (LDX) in adult stimulant abusers. 2006. Nov 17, Poster presented at the 2006 U.S. Psychiatric & Mental Health Congress. New Orleans. 25. Jasinski D, Krishnan S. Abuse liability of intravenous lisdexamfetamine dimesylate (LDX; NRP104) 2006. Nov 17, Poster presented at the 2006 U.S. Psychiatric & Mental Health Congress. New Orleans. 26. [July 24, 2007]. Vyvanse Prescribing Information. Available at: www.vyvanse.com/pdf/prescribing_information.pdf. Articles from Psychiatry (Edgmont) are provided here courtesy of Matrix Medical Communications Redigera Google Translate för företag:ÖversättningsverktygWebbplatsöversättareGlobal Market Finder Inaktivera snabböversättningOm Google ÖversättMobilSekretessHjälpSkicka feedbackLogo of springeropen Attention Deficit and Hyperactivity Disorders Atten Defic Hyperact Disord. 2013; 5: 249–265. Published online Apr 6, 2013. doi: 10.1007/s12402-013-0106-x PMCID: PMC3751218 Long-acting stimulants for treatment of attention-deficit/hyperactivity disorder: a focus on extended-release formulations and the prodrug lisdexamfetamine dimesylate to address continuing clinical challenges Frank A. López and Jacques R. Lerouxcorresponding author Author information ► Article notes ► Copyright and License information ► Go to: Abstract Individuals with attention-deficit/hyperactivity disorder (ADHD) show pervasive impairments across family, peer, and school or work functioning that may extend throughout the day. Psychostimulants are highly effective medications for the treatment of ADHD, and the development of long-acting stimulant formulations has greatly expanded the treatment options for individuals with ADHD. Strategies for the formulation of long-acting stimulants include the combination of immediate-release and delayed-release beads, and an osmotic-release oral system. A recent development is the availability of the first prodrug stimulant, lisdexamfetamine dimesylate (LDX). LDX itself is inactive but is cleaved enzymatically, primarily in the bloodstream, to release d-amphetamine (d-AMP). Several clinical trials have demonstrated that long-acting stimulants are effective in reducing ADHD symptoms compared with placebo. Analog classroom and simulated adult workplace environment studies have shown that long-acting stimulants produce symptom reduction for at least 12 h. Long-acting stimulants exhibit similar tolerability and safety profiles to short-acting equivalents. While variations in gastric pH and motility can alter the availability and absorption of stimulants released from long-acting formulations, the systemic exposure to d-AMP following LDX administration is unlikely to be affected by gastrointestinal conditions. Long-acting formulations may also improve adherence and lower abuse potential compared with their short-acting counterparts. The development of long-acting stimulants provides physicians with an increased range of medication options to help tailor treatment for individuals with ADHD. Keywords: Attention-deficit hyperactivity disorder, Central nervous system stimulants, Amphetamines, Methylphenidate, Treatment efficacy, Safety Go to: Introduction Attention-deficit/hyperactivity disorder (ADHD) is a common neurobehavioral disorder that is estimated to affect 5–12 % of children and persists into adulthood in more than half of cases (Biederman and Faraone 2005; Polanczyk et al. 2007). ADHD is characterized by the core symptoms of inattention, hyperactivity, and impulsivity (American Psychiatric Association 2000). In addition, individuals with ADHD exhibit functional impairments that include poor intrafamily interactions, low academic achievement and conduct problems in children and adolescents, and increased risk of lower educational attainment, behavior leading to arrests and traffic violations, unemployment, and divorce in adults (Able et al. 2007; Barkley et al. 2006; Biederman et al. 2006a; Kessler et al. 2006; Klassen et al. 2004; Sawyer et al. 2002). Clinical guidelines for the treatment for ADHD generally recommend an individualized, multimodal plan which includes pharmacotherapy, behavioral, and educational interventions (American Academy of Pediatrics 2011; Canadian Attention Deficit Hyperactivity Disorder Resource Alliance (CADDRA) 2011; National Institute for Health and Clinical Excellence 2009; Pliszka 2007). For many years, short-acting formulations of the psychostimulants methylphenidate (MPH) and amphetamine (AMP) were the mainstay of ADHD pharmacotherapy. However, despite their well-documented efficacy, durations of action in the range 3–6 h posed significant challenges and limitations in their treatment for ADHD (Antshel et al. 2011). The requirement for repeated dosing during the day may cause embarrassment and stigma for the patient, difficulties associated with storing scheduled drugs, especially in a school environment, fragmented coverage, poor adherence, and the potential for the diversion of drug for non-medical use (Swanson 2003; Wolraich et al. 2001). In response to these challenges, long-acting psychostimulants were developed to relieve ADHD symptoms throughout the day without the need for repeat dosing and to improve adherence compared with short-acting agents (Adler and Nierenberg 2010; Christensen et al. 2010; Ramos-Quiroga et al. 2008; Spencer et al. 2011; van den Ban et al. 2010). The variation in the pharmacokinetic properties of the different formulations of long-acting psychostimulant therapies is reflected in their pharmacodynamic properties including their onset, magnitude, and duration of symptom relief. Treatment strategies should be based on an understanding of the efficacy and safety profile of each formulation, paired with individual patient needs. Long-acting psychostimulants, as well as the non-stimulant atomoxetine, are recommended as first-line pharmacotherapies in many countries for the management of ADHD in children, adolescents, and adults (American Academy of Pediatrics 2011; Canadian Attention Deficit Hyperactivity Disorder Resource Alliance (CADDRA) 2011; National Institute for Health and Clinical Excellence 2009; Pliszka 2007). This article will review the different controlled-release and prodrug delivery systems of long-acting stimulants, and examine the impact of these formulations on their pharmacokinetics, efficacy, safety, and adherence. Go to: Long-acting stimulant formulations The long-acting psychostimulants that have been approved for the treatment for ADHD can be categorized according to the technology that has been utilized to extend or delay the release of the active agent (Fig. 1) (Table ​(Table1).1). The first generation of long-acting stimulants included sustained-release formulations of MPH (MPH-SR) that utilized a wax-matrix-based technology to deliver a single, prolonged pulse of MPH. With a duration of action of up to 8 h, some authors consider these preparations to be intermediate- rather than long-acting (Dopheide 2009), and their efficacy may be inferior to multiple-dose regimens of the immediate-release formulations (Swanson and Volkow 2009). The flat (zero-order) drug delivery profile of MPH-SR may account for the development of acute drug tolerance in response to exposure to relatively high drug levels over a prolonged period (Swanson 2003). Fig. 1 Fig. 1 Delivery systems of long-acting psychostimulants used in the treatment for ADHD. Not shown are the delivery systems of MPH-SR and Novo-MPH ER-C. MPH-SR is an extended-release formulation in tablet form that uses a wax-based matrix to achieve prolonged ... Table 1 Table 1 Summary of mean (SD) pharmacokinetic parameters observed for selected long-acting stimulants Several controlled-release (CR) stimulant formulations were developed that combined a rapid onset of action with extended coverage throughout the day. One strategy for the biphasic delivery of stimulants is to mix beads with different drug release profiles. CR capsules contain beads that incorporate MPH (MPH-CR) or d-AMP (AMP-CR) with distinct immediate- and delayed-release profiles (Fig. 1). CR-mixed AMP salts comprise equal proportions of four AMP salts, d-AMP saccharate, d,l-AMP aspartate monohydrate, d-AMP sulfate, and d,l-AMP sulfate. Each capsule contains immediate-release and enteric-coated delayed-release beads in a 1:1 ratio (Shire Canada Inc.; Tulloch et al. 2002). Several stimulant drugs are based on combinations of beads with immediate- and extended-release profiles, but the proportions of the total dose of active ingredient in the two phases of delivery vary. An alternative technology designed to deliver the controlled and biphasic delivery of stimulant medication is the osmotic-release oral system methylphenidate (OROS-MPH). OROS-MPH utilizes osmotic pressure to control the rate of delivery of the active ingredient, racemic MPH. Each capsule consists of a three-compartment core that is enclosed by a semipermeable membrane that, in turn, is surrounded by a drug overcoat (Fig. 1). After ingestion, the drug overcoat provides immediate release of MPH (22 % of the dose) (McBurnett and Starr 2011). Aqueous fluid enters the osmotic pump compartment from the gastrointestinal tract and delivers the remaining dose at a first-order rate from the core through a laser-drilled exit port (Janssen Inc.; Swanson et al. 2004). A concentration gradient exists between the two drug compartments, which also modifies the rate of drug release. OROS-MPH has a smooth ascending plasma concentration profile, which is thought to minimize the development of acute tolerance and maintain full efficacy across the day (Swanson et al. 2003). Lisdexamfetamine dimesylate (LDX) is the first prodrug stimulant. Rather than utilizing a mechanical or physical mechanism to achieve a prolonged duration of action, LDX is a prodrug in which d-AMP is covalently bound to the amino acid lysine. LDX itself is therapeutically inactive but, after oral administration, enzymatic hydrolysis of LDX releases the therapeutically active moiety d-AMP (Pennick 2010). The rate of enzymatic conversion controls the rate at which d-AMP becomes available. The resulting pharmacokinetic profile is dose-proportional and monophasic and reflects the gradual conversion of LDX to d-AMP over the post-dose period (Boellner et al. 2010). As enzymatic hydrolysis occurs mostly in the bloodstream (Pennick 2010), the metabolic conversion of LDX to d-AMP is unlikely to be affected by variations in gastric pH or gastrointestinal transit time (Ermer et al. 2010b; Haffey et al. 2009; Krishnan and Zhang 2008). Thus, pharmacokinetic studies have shown that the rate of d-AMP absorption and metabolism is more consistent and predictable between and within individuals with LDX than with extended-release mixed amphetamine salts (MAS-XR) (Biederman et al. 2007a; Ermer et al. 2010a). Furthermore, the rate of d-AMP delivery following administration of LDX is reported to be unaffected by concurrent administration of the acid-suppressing drug omeprazole, whereas a shortened time to peak concentration of d-AMP was observed when MAS-XR was taken with omeprazole (Haffey et al. 2009) (Table 1). Go to: Efficacy of long-acting stimulants Clinical trial evidence supports the efficacy of long-acting stimulants. Tables 2 and ​and33 present a summary of short-term (≤13-weeks), randomized, controlled clinical efficacy trials of long-acting psychostimulants. The control of symptoms throughout the day and into the early evening is likely to be an important factor in the overall efficacy of ADHD pharmacotherapies (Coghill et al. 2008). Table 2 Table 2 Short-term (≤13-week), randomized, controlled clinical efficacy trials of long-acting methylphenidate-based stimulants in children and adults with ADHD Table 3 Table 3 Short-term (≤13-week), randomized, controlled clinical efficacy trials of long-acting amphetamine-based psychostimulants in children and adults with ADHD Methylphenidate sustained-release There are limited clinical trial data of MPH-SR in children with ADHD (Table 2). In a comparison of immediate-release MPH (MPH-IR), with MPH-SR, controlled-release d-AMP, and pemoline in boys with ADHD, sustained-release MPH demonstrated efficacy versus placebo in some behavioral measures, some performance-based tasks, and structured assessments by counselors on the Abbreviated Conners’ Teachers Rating Scale (ACTRS), but not on the teacher-rated ACTRS (Pelham et al. 1990). MPH-SR has a duration of effect of approximately 8 h (Novartis Pharmaceuticals Canada Inc.). Methylphenidate controlled-release MPH-CR has shown significant efficacy in reducing ADHD symptoms (Table 2). In children with ADHD, both MPH-CR and IR-MPH yielded similar, statistically significant reductions from baseline in Conners’ Parent Rating Scale-Revised scores (CPRS-R)(Weiss et al. 2007). However, superior symptom reduction with IR-MPH versus MPH-CR was observed based on Conners’ Teacher Rating Scale-Revised (CTRS-R). In adults with ADHD, MPH-CR yielded significantly better Clinical Global Impressions-Improvement (CGI-I) ratings versus placebo after 2 weeks (Jain et al. 2007). Using an analog classroom crossover protocol, Schachar et al. (2008) compared MPH-CR and IR-MPH with placebo in children with ADHD. Significant improvements versus placebo were seen with MPH-CR for up to 10 h post-dosing, based on change from baseline on Inattention/Overactivity With Aggression-Conners’ scale (IOWA-C) overall and subscores for inattention/overactivity and aggression/defiance. Osmotic-release oral system methylphenidate OROS-MPH has demonstrated efficacy in ADHD symptom reduction in children, adolescents, and adults (Table 2). In a 4-week, parallel-group, placebo-controlled study, OROS-MPH was significantly more effective than placebo in children with ADHD, based on endpoint scores for the Inattention/Overactivity subscale of the IOWA Conners’ Teacher Rating Scale (Wolraich et al. 2001). In a 2-week, parallel-group study, OROS-MPH significantly reduced ADHD Rating Scale IV (ADHD-RS-IV) scores in adolescents with ADHD compared with placebo (Wilens et al. 2006a). Similar improvements compared with placebo in the symptoms of ADHD have been described in adults treated with OROS-MPH (Adler et al. 2009; Biederman et al. 2006b; Medori et al. 2008). In a head-to-head trial, subtle variations of timing and magnitude of symptom control were observed between MPH-CD and OROS-MPH. Although MPH-CD showed greater efficacy in the morning hours, OROS-MPH exhibited longer-lasting efficacy, extending up to 12 h following a single morning dose (Pelham et al. 2001). Head-to-head comparisons of long-acting MPH (MPH-LA) and OROS-MPH in children with ADHD using analog classroom protocols over 8–12 h found that both active treatments improved Permanent Product Measure of Performance (PERMP) math test scores for the number of problems answered correctly (PERMP-C) (Lopez et al. 2003) and Swanson, Kotkin, Agler, M-Flynn, and Pelham Rating Scale (SKAMP)-deportment and SKAMP-Attention scores (Silva et al. 2005). While both treatments were generally effective and well tolerated, superiority of one treatment over the other in such laboratory school settings is dependent on the formulation with the highest expected plasma MPH concentration across the post-dosing period (Swanson et al. 2004). Placebo-controlled analog classroom studies indicate that OROS-MPH has a duration of action of at least 12.5 h (the last time point assessed) in children with ADHD (Armstrong et al. 2012; Murray et al. 2011; Wigal et al. 2011). Mixed amphetamine salts extended-release A number of randomized controlled clinical trials have shown that controlled-release MAS (MAS-CR) is effective versus placebo for reducing ADHD symptoms in children, adolescents, and adults (Table 3) (Biederman et al. 2002; Spencer et al. 2006b; Weisler et al. 2006). An analog classroom trial in children showed that a significant effect of MAS-CR over placebo emerged at 1.5 h post-dosing and was maintained for up to 12 h, based on improvements from baseline at end point in SKAMP-D and math test scores (McCracken et al. 2003). Dextroamphetamine controlled-release Studies of the efficacy of controlled-release AMP (AMP-CR) in participants with ADHD are limited. Pelham et al. compared treatment arms with AMP-CR, IR-MPH, MPH-SR, and pemoline in boys. Although all treatments were superior to placebo in some behavioral measures, only pemoline and AMP-XR were superior to placebo by the teacher-rated ACTRS. The duration of efficacy was characterized as within 2 h of ingestion and up to 9 h post-dose (Pelham et al. 1990). In an analog classroom trial of AMP-CR in children, objective actometer measures and parent ratings of behavior were improved compared with placebo from 1.75 to 12 h following a single morning dose. The effects of AMP-CR were “less robust” than those of IR-MAS in the morning hours after dosing but were extended for 3–6 h longer (James et al. 2001). Lisdexamfetamine dimesylate The efficacy of LDX compared with placebo in reducing the symptoms of ADHD has been demonstrated in patients across the lifespan (Table 3). In 4-week trials of LDX 30, 50, and 70 mg in children, adolescents, and adults with ADHD, all doses of LDX demonstrated significant improvements in ADHD-RS-IV scores compared with placebo (Adler et al. 2008; Biederman et al. 2007b; Findling et al. 2011). Mean rates of response (defined as >30 % improvement in ADHD-RS-IV scores and CGI-I ratings of much improved or very much improved) were approximately 80 % at end point in children treated with LDX 70 mg compared with less than 20 % for placebo (Biederman et al. 2007b). Furthermore, improvements compared to placebo in CPRS-R scores in children with ADHD were maintained until 6 pm following an early morning dose (Biederman et al. 2007b). In an analog classroom study in children with ADHD, the therapeutic effects of LDX extended from 1.5 to 13 h post-dose (the first and last time points assessed) based on improvements in SKAMP and PERMP scores (Wigal et al. 2009). In a simulated adult workplace environment study, the therapeutic effects of LDX were maintained from 2 to 14 h post-dose (the first and last time points measured) in adults with ADHD, as shown by improvements in PERMP scores versus placebo (Wigal et al. 2010). The demonstration that the efficacy of LDX is maintained for at least 13 h in children and 14 h in adults suggests that this prodrug may be the longest-acting stimulant treatment for ADHD.

Meta-analyses of the effectiveness of long-acting stimulants

Meta-analyses have compared efficacy outcomes from multiple studies of different stimulant formulations (Faraone 2009, 2012; Faraone and Glatt 2010). In an analysis of 32 trials of 16 medications in youths with ADHD, the mean effect size for long-acting stimulants was 0.95 compared with 0.99 for immediate-release stimulants (Faraone 2009). Similarly, in 19 trials of 13 ADHD drugs in adults, mean effect sizes were 0.73 and 0.96 for long-acting and immediate-release stimulants, respectively (Faraone and Glatt 2010). A meta-analysis of efficacy studies in children with ADHD, based only on ADHD Rating Scale and Clinical Global Impressions outcomes, found that a pooled effect size for LDX of approximately 1.5 was significantly (p < 0.001) greater than the pooled effect size of the other medications (Faraone 2012). In adult studies, LDX effect sizes were similar to those of other medications. Using numbers-needed-to-treat (NNT) to compare the efficacy of stimulants medications across 23 clinical trials in children and adolescents, NNT (95 % confidence intervals) were slightly lower (i.e., fewer patients were required to see a positive effect) for formulations of AMP (2.0 [1.7, 2.2]) than MPH (2.6 [2.4, 2.8]), although mean NNT values were not calculated for long-acting and immediate-release formulations (Faraone et al. 2006). Go to: Safety of psychostimulants Short- and long-acting psychostimulants share similar adverse event profiles (Banaschewski et al. 2006). Adverse events most commonly associated with the use of psychostimulants to treat ADHD include neurological (headache, dizziness, insomnia, seizures), psychiatric (mood/anxiety, tics, psychosis), and gastrointestinal (abdominal pain, poor appetite leading to weight loss/slowed growth) effects. In general, these events are mild and/or temporary (Graham et al. 2011). Areas of particular concern in the use of psychostimulants to treat ADHD include their effects on growth and cardiovascular parameters, and their potential for abuse. Effect on weight and growth An analysis of 20 longitudinal studies found that long-term psychostimulant use in children with ADHD resulted in statistically significant delays in growth versus age-related norms (Faraone et al. 2008). Effects appeared to be dose-related, were more apparent for weight than height, were similar between MPH and AMP formulations, and, in many cases, appeared to normalize over time despite continued treatment (Faraone et al. 2008). In the MTA (Multimodal Treatment Study of Children with ADHD), the largest longitudinal study of children with ADHD, average relative size of patient (a composite of height and weight as z scores) was negatively related to the average cumulative exposure to psychostimulants. Growth slowing for newly medicated versus untreated participants was found for the first 14 months, was attenuated at 24 months, and was non-significant at 36 months (Murray et al. 2008; Swanson et al. 2007). Nevertheless, it is recommended that height and weight are monitored in patients receiving stimulant medications, including long-acting formulations. Cardiovascular events Cardiovascular safety concerns with psychostimulant ADHD medications were raised based on rare occurrences of sudden death and other cardiac events (Vetter et al. 2008). Psychostimulants modulate cardiovascular contractility and heart rate via sympathomimetic effects (Wilens et al. 2006b), and changes in vital signs have been noted with MPH and AMP treatments, including increases in systolic and diastolic blood pressure (~2–6 mmHg) and heart rate (~8 beats per minute) (Wilens et al. 2005). In clinical trials of psychostimulants in children and adults, no clinically significant changes in atrial or ventricular conduction or repolarization have been observed (Wilens et al. 2006b). An elevated risk of cardiac-related emergency visits with current psychostimulant use versus non-use has been reported (Winterstein et al. 2007; Winterstein et al. 2009), but in the majority of healthy children with no history of or current cardiovascular abnormalities, psychostimulants produced cardiovascular effects of minimal clinical significance (Findling et al. 2001, 2005; Safer 1992; Wilens et al. 2006b). Similarly, a large, retrospective, population-based cohort study concluded that ADHD medication use in children and young and middle-aged adults was not associated with an increased risk of serious cardiovascular events compared with non-use (Cooper et al. 2011; Habel et al. 2011). However, when treatment with any psychostimulant formulation is contemplated in a patient with structural heart disease, or in a patient who has a personal or a family history of syncope or sudden death, respectively, a pediatric or cardiologic consultation prior to ADHD pharmacological treatment is strongly advised (Graham et al. 2011). Abuse, misuse, and diversion Prescription stimulants are classified as controlled substances, and their abuse, misuse, and diversion are important public health and safety concerns (Kollins 2008; Wilens et al. 2008). Since euphoria and drug “liking” are linked to a more rapid rate of absorption and delivery to the brain (Volkow and Swanson 2003), it follows that controlling the rate of stimulant release may modify its potential for abuse. Support for a lower abuse potential for long-acting compared with short-acting stimulants includes greater subjective responses for immediate-release stimulants than OROS-MPH in healthy adults (Parasrampuria et al. 2007; Spencer et al. 2006a). The formulation of stimulants as once-daily medications also reduces the likelihood of diversion by removing the requirement for drug administration at school. Many long-acting stimulants can be manipulated to facilitate more rapid absorption of the active ingredient, for example by crushing or dissolving the medications in order to facilitate intranasal or parenteral administration (Mao et al. 2011). However, the physical characteristics of stimulant formulations, such as the non-deformable shell of the OROS-MPH capsule, may make them more difficult to break, cut, or crush. The prodrug design of LDX means that the rate of active d-AMP release is limited by the rate of enzymatic conversion, regardless of the route of drug administration or capsule intactness. Thus, the plasma concentration–time profile of intranasal LDX in healthy men is similar to that following oral administration (Ermer et al. 2011). In individuals with a history of stimulant abuse, scores in the Drug Rating Questionnaire-Subject liking scale for oral LDX (≤100 mg) were no different to placebo, whereas the equivalent oral dose of d-AMP (40 mg) was favored over placebo (Jasinski and Krishnan 2009a). Similarly, unlike intravenous d-AMP 20 mg, an equivalent intravenous dose of LDX (50 mg) did not produce subjective abuse-related liking scores (Jasinski and Krishnan 2009a, b). Go to: Adherence Non-adherence to medication for chronic illnesses is estimated to be approximately 50 % (World Health Organization 2003). In ADHD, the prevalence of medication discontinuation or non-adherence is reported to range from 13 to 64 % (Adler and Nierenberg 2010). After 14 months of treatment with MPH in the MTA study, analysis of saliva samples indicated that only 53.5 % of patients were adherent at every assay point and that almost 25 % of patients were non-adherent at 50 % or more of their assays (Pappadopulos et al. 2009). Studies that have examined the impact of formulation on adherence and persistence of stimulant medications for ADHD include several retrospective claims analyses (Christensen et al. 2010; Marcus et al. 2005; Sanchez et al. 2005). The largest of these identified over 60,000 newly treated patients with ADHD (Christensen et al. 2010). This analysis indicated that the mean (SD) adherence (defined as the ratio of the number of days therapy supplied to the total number of days persistent) to long-acting stimulants (0.56 [0.32]) was significantly greater (p < 0.0001) than that for short- (0.43 [0.35]) and intermediate-acting (0.47 [0.35]) stimulants. Similarly, the mean (SD) persistence (defined as the number of days out of 365 days plus the index day that the patient remained on their index therapy) on long-acting stimulants (239.5 [145.8]) was significantly greater (p < 0.0001) than for short- (186.7 [154.8]) or intermediate-acting (185.6 [153.4]) stimulants (Christensen et al. 2010). Furthermore, a chart review of Spanish adults with ADHD found that the switch from short-acting MPH to long-acting MPH was associated with a significant improvement in all items of the Simplified Medication Adherence Questionnaire (Ramos-Quiroga et al. 2008). These data suggest that the choice of formulation has important consequences on the adherence and persistence of ADHD stimulant medications. Go to: Treatment individualization Evidence-based ADHD guidelines recognize that medication strategies should be tailored for the individual. Among the factors to consider when selecting an appropriate medication for a patient with ADHD are drug class and the formulation required to give the desired pharmacokinetic and pharmacodynamic profiles. The choice of medications for ADHD includes both stimulants and non-stimulants. With regard to stimulants, although mean responses to MPH and AMP are similar, individuals may respond differently to the two drugs. As reviewed by Arnold (2000), approximately 28 % will respond preferentially to AMP, 17 % will respond preferentially to MPH, and less than 13 % will not respond to either (Arnold 2000). Where stimulant medications are indicated, the selection of formulation should be based both on clinical requirements and on the preferences of the patient and/or their family. Short- and long-acting formulations provide treatment options ranging from approximately 4 h to, in the case of LDX, more than 13 h in children (Wigal et al. 2009) and more than 14 h in adults (Wigal et al. 2010). It is important to note that suboptimal response to one class or formulation of stimulant does not predict failure of another. Thus, a recent post hoc analysis found that the clinical effectiveness and rates of remission in children with ADHD who were treated with LDX were similar in patients with a previous suboptimal response to MPH treatment to those of the overall study population (Jain et al. 2011). Go to: Conclusions The development of controlled-release formulations of stimulants and the stimulant prodrug LDX has greatly increased the number of pharmacological treatment options for patients with ADHD. At equivalent systemic exposures, the efficacy and safety of long-acting stimulants appear to be equivalent to short-acting formulations. However, long-acting medications offer several potential benefits to patients. Long-acting stimulants offer efficacy for at least 13–14 h without augmentation. The convenience of once-daily dosing may contribute to improved adherence of long-acting stimulants compared with short-acting stimulants. Prodrug technology may also provide lower inter- and intra-patient variability in exposure than mechanical controlled-release systems. Furthermore, long-acting stimulants may be less prone to abuse than their short-acting counterparts. Thus, the development of long-acting formulations of stimulants provides important additional treatment options for the management of ADHD. Go to: Acknowledgments The authors wish to pay tribute to their late colleague, Atilla Turgay, MD, and recognize his contributions to earlier drafts of this article. The content of this manuscript, the ultimate interpretation, and the decision to submit it for publication in ADHD Attention Deficit and Hyperactivity Disorders were made independently by the authors. Writing and editing support for this manuscript was provided by Ogilvy CommonHealth Scientific Communications and Oxford PharmaGenesis™ Ltd and funded by Shire Development LLC. Conflict of interest Frank A. 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[PubMed] [Cross Ref] Swanson JM, Elliott GR, Greenhill LL, Wigal T, Arnold LE, Vitiello B, Hechtman L, Epstein JN, Pelham WE, Abikoff HB, Newcorn JH, Molina BS, Hinshaw SP, Wells KC, Hoza B, Jensen PS, Gibbons RD, Hur K, Stehli A, Davies M, March JS, Conners CK, Caron M, Volkow ND. Effects of stimulant medication on growth rates across 3 years in the MTA follow-up. J Am Acad Child Adolesc Psychiatry. 2007;46(8):1015–1027. doi: 10.1097/chi.0b013e3180686d7e. [PubMed] [Cross Ref] Tulloch SJ, Zhang Y, McLean A, Wolf KN. SLI381 (Adderall XR), a two-component, extended-release formulation of mixed amphetamine salts: bioavailability of three test formulations and comparison of fasted, fed, and sprinkled administration. Pharmacotherapy. 2002;22(11):1405–1415. doi: 10.1592/phco.22.16.1405.33687. [PubMed] [Cross Ref] van den Ban E, Souverein PC, Swaab H, van Engeland H, Egberts TC, Heerdink ER. 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Misuse and diversion of stimulants prescribed for ADHD: a systematic review of the literature. J Am Acad Child Adolesc Psychiatry. 2008;47(1):21–31. doi: 10.1097/chi.0b013e31815a56f1. [PubMed] [Cross Ref] Winterstein AG, Gerhard T, Shuster J, Johnson M, Zito JM, Saidi A. Cardiac safety of central nervous system stimulants in children and adolescents with attention-deficit/hyperactivity disorder. Pediatrics. 2007;120(6):e1494–e1501. doi: 10.1542/peds.2007-0675. [PubMed] [Cross Ref] Winterstein AG, Gerhard T, Shuster J, Saidi A. Cardiac safety of methylphenidate versus amphetamine salts in the treatment of ADHD. Pediatrics. 2009;124(1):e75–e80. doi: 10.1542/peds.2008-3138. [PMC free article] [PubMed] [Cross Ref] Wolraich ML, Greenhill LL, Pelham W, Swanson J, Wilens T, Palumbo D, Atkins M, McBurnett K, Bukstein O, August G. Randomized, controlled trial of OROS methylphenidate once a day in children with attention-deficit/hyperactivity disorder. Pediatrics. 2001;108(4):883–892. doi: 10.1542/peds.108.4.883. [PubMed] [Cross Ref] Adherence to long-term therapies: evidence for action. Geneva: World Health Organization; 2003. Articles from Springer Open Choice are provided here courtesy of Springer CNS Drugs. 2014; 28: 497–511. Published online May 1, 2014. doi: 10.1007/s40263-014-0166-2 PMCID: PMC4057639 A Systematic Review of the Safety of Lisdexamfetamine Dimesylate David R. Coghill,corresponding author Beatriz Caballero, Shaw Sorooshian, and Richard Civil Author information ► Copyright and License information ► Go to: Abstract Background Here we review the safety and tolerability profile of lisdexamfetamine dimesylate (LDX), the first long-acting prodrug stimulant for the treatment of attention-deficit/hyperactivity disorder (ADHD). Methods A PubMed search was conducted for English-language articles published up to 16 September 2013 using the following search terms: (lisdexamfetamine OR lisdexamphetamine OR SPD489 OR Vyvanse OR Venvanse OR NRP104 NOT review [publication type]). Results In short-term, parallel-group, placebo-controlled, phase III trials, treatment-emergent adverse events (TEAEs) in children, adolescents, and adults receiving LDX were typical for those reported for stimulants in general. Decreased appetite was reported by 25–39 % of patients and insomnia by 11–19 %. The most frequently reported TEAEs in long-term studies were similar to those reported in the short-term trials. Most TEAEs were mild or moderate in severity. Literature relating to four specific safety concerns associated with stimulant medications was evaluated in detail in patients receiving LDX. Gains in weight, height, and body mass index were smaller in children and adolescents receiving LDX than in placebo controls or untreated norms. Insomnia was a frequently reported TEAE in patients with ADHD of all ages receiving LDX, although the available data indicated no overall worsening of sleep quality in adults. Post-marketing survey data suggest that the rate of non-medical use of LDX was lower than that for short-acting stimulants and lower than or equivalent to long-acting stimulant formulations. Small mean increases were seen in blood pressure and pulse rate in patients receiving LDX. Conclusions The safety and tolerability profile of LDX in individuals with ADHD is similar to that of other stimulants. Go to: Key Points Table thumbnail Go to: Introduction Stimulants are recommended by European and North American guidelines as a first-line medication option for children and adolescents (aged 6–17 years) with attention-deficit/hyperactivity disorder (ADHD) [1–3], and are also recommended in some guidelines for the treatment of adults with the disorder [2, 4]. A range of amphetamine (AMP)- and methylphenidate (MPH)-based stimulants, as well as the non-stimulants atomoxetine (ATX), guanfacine, and clonidine, are available for the treatment of ADHD in North America and several European countries [5]. Numerous studies have shown stimulants to be effective in reducing the core symptoms and behavioral impairments associated with ADHD [1, 6]. In a meta-analysis of 32 double-blind, placebo-controlled trials of ADHD medications in patients aged 6–18 years, effect sizes were shown to be significantly greater for stimulants than for non-stimulants [7]. A second meta-analysis of 23 double-blind, placebo-controlled trials of stimulant medications for ADHD in children and adolescents found that effect sizes compared with placebo were modestly but statistically significantly greater for AMP-based stimulants than for MPH [8]. Various long-acting AMP- and MPH-based stimulants have been developed, with the aim of relieving ADHD symptoms throughout the day using a once-daily dose [9]. Lisdexamfetamine dimesylate (LDX) is the first long-acting prodrug stimulant for the treatment of ADHD [10]. After ingestion and absorption, LDX is enzymatically hydrolyzed to release the therapeutically active moiety d-AMP, and the essential amino acid lysine [11]. As hydrolysis of LDX occurs mainly in the blood, the generation of d-AMP is unlikely to be affected by either gastrointestinal pH or transit time [12–14]. Pharmacokinetic studies in humans have shown that exposure to d-AMP following oral administration of LDX is monophasic, sustained, and dose-proportional, with low intra- and inter-patient variability [12, 15, 16]. This profile of systematic exposure to d-AMP facilitates dose optimization by reducing the likelihood of sub- or supra-therapeutic levels [17]. The pharmacodynamic properties of LDX are reflected in clinical analog classroom studies and simulated adult workplace studies that have shown that, following a single dose of LDX, therapeutic effects are observed through to the last assessment of the day; 13 h post dose in children and 14 h post dose in adults [18, 19]. In a series of randomized, controlled trials, effect sizes for LDX have been shown to be greater than those for MPH-based stimulants in the treatment of children and adolescents with ADHD [8], and a post hoc analysis of data from a randomized, placebo- and active-controlled phase III clinical trial showed that improvements in the symptoms of ADHD were statistically significantly greater in patients receiving LDX than in those receiving the reference therapy osmotic-release oral system MPH (OROS-MPH) [20]. The safety warnings for LDX are similar to those for other stimulant treatments for ADHD [21]. In this review, we examine the safety and tolerability profile of LDX. We begin by analyzing the treatment-emergent adverse events (TEAEs) and vital signs data recorded in clinical trials of LDX, of both short- and longer-term duration. We then focus down on evidence relating to four specific safety concerns associated with stimulant ADHD pharmacotherapies, namely reduced weight and growth, sleep disruption, abuse liability, and cardiovascular events [3, 5, 22]. Go to: Methods A PubMed search was conducted using the following search terms: (lisdexamfetamine OR lisdexamphetamine OR SPD489 OR Vyvanse OR Venvanse OR NRP104 NOT review [publication type]). The final iteration of the search was conducted on 16 September 2013. The search was not limited by publication date but was limited to English language articles. The above search terms were subsequently used in conjunction with the following additional terms (applied individually): AND ADHD, AND abuse liability, AND cardiovascular safety, AND sleep, AND weight, AND growth. Of 129 references identified, 35 contained LDX safety and tolerability data in patients with ADHD (Fig. 1). Fig. 1 Fig. 1 Systematic review flowchart to identify safety outcomes reported in lisdexamfetamine dimesylate clinical trials. ADHD attention-deficit/hyperactivity disorder Go to: Results Safety and Tolerability in Short-Term Trials Randomized, Parallel-Group, Double-Blind Trials in Patients with Attention-Deficit/Hyperactivity Disorder (ADHD) The efficacy and safety of LDX in the treatment of ADHD were evaluated in six randomized, parallel-group, double-blind, phase III trials (Table 1) [23–28]. Three trials (studies 301, 303, and 305), were forced-dose titration studies in which patients were randomized to receive once-daily LDX 30, 50, or 70 mg, or placebo for 4 weeks [23, 24, 26]. In these trials, dose increases followed a predefined schedule: patients randomized to LDX 30 mg received this dose throughout the study; patients randomized to LDX 50 mg received 30 mg/day during week 1 and 50 mg/day during weeks 2–4; patients randomized to LDX 70 mg received 30 mg/day during week 1, 50 mg/day during week 2, and 70 mg/day during weeks 3–4. The remaining three trials utilized dose-optimization protocols: study 403 was placebo controlled, study 325 was placebo and active (OROS-MPH) controlled, and study 317 was a head-to-head comparison of LDX and ATX. In these studies, patients randomized to LDX were individually optimized to LDX 30, 50, or 70 mg/day during weeks 1–4 based on efficacy and tolerability [25, 27, 28]. Patients randomized to the reference treatment OROS-MPH in study 325 were individually optimized to 18, 36, or 54 mg/day (OROS-MPH was administered according to European regulations with a maximum licensed dose of 54 mg/day) [25]. Patients randomized to the control treatment ATX in study 317 were optimized to 0.5–1.2 mg/kg (with a maximum daily dose of 1.4 mg/kg) if under 70 kg in weight, or 40, 80, or 100 mg/day in patients weighing 70 kg or over [27]. Table 1 Table 1 Most frequently reported treatment-emergent adverse events in randomized, double-blind, parallel-group clinical trials of lisdexamfetamine dimesylate [23–28] The overall rates of TEAEs for LDX-treated patients were generally similar across age groups and were typical of those previously reported for stimulants in general [3, 5, 22]. The overall frequency of TEAEs for LDX-treated patients did not differ greatly between studies with durations of 4 weeks or 7–10 weeks (Table 1). This may have been because most TEAEs are reported to occur within 4 weeks of treatment initiation [18, 19, 23, 24, 29, 30]. It is also possible that the dose-optimized design of studies 317, 325, and 403 may have reduced the rate of TEAEs compared with the forced-dose titration design of the three shorter trials. The most common TEAEs reported in patients receiving LDX in these short-term trials are shown in Table 1. In all studies, decreased appetite was the most common TEAE and was reported by ≥25 % (range 25.2–39.0) of patients treated with LDX, irrespective of age. Weight loss was reported in 9.2–21.9 % of children and adolescents receiving LDX, but was not consistently reported as a common TEAE in adult studies. Anorexia was reported in 10.8 % of children and adolescents receiving LDX in study 325 but by 5.1 % or less in the adult studies. Insomnia was common in all age groups, occurring in 11–19 % of LDX-treated patients. Dry mouth was a prominent TEAE in adults treated with LDX (25.7–31.6 %) but was reported in <7 % of children and adolescents. Nausea was reported in 2.5–12.5 % of patients receiving LDX. Although headache and nasopharyngitis were commonly reported TEAEs, their frequency did not differ greatly between the LDX and placebo groups in any trial. With regard to active treatment controls, headache, decreased appetite, and nasopharyngitis were reported by more than 10 % of patients receiving OROS-MPH in study 325, and decreased appetite, fatigue, headache, nausea, and somnolence were reported by more than 10 % of patients receiving ATX in study 317. Across all studies, the percentage of patients who discontinued treatment owing to a TEAE ranged from 4.3 to 9.2 % in the LDX treatment groups, compared with 1.3–3.6 % in the placebo groups, 7.5 % in the ATX group of study 317, and 1.8 % in the OROS-MPH group of study 325 (Table 1). In the placebo-controlled studies, TEAEs leading to discontinuation in at least 1 % of patients receiving LDX were as follows: ventricular hypertrophy as determined by electrocardiography (ECG), tic, vomiting, psychomotor hyperactivity, insomnia, and rash in study 301 in children; irritability, decreased appetite and insomnia in study 305 in adolescents; insomnia, tachycardia, irritability, hypertension, headache, anxiety, and dyspnea in study 303 in adults; and rectal fissure, fatigue, irritability, influenza, and decreased libido/erectile dysfunction also in adults [21, 23, 28]. In the ATX-controlled study in children and adolescents (study 317), the TEAEs leading to discontinuation were agitation, decreased weight, excoriation, indifference, irritability, somnolence, nausea, and tic in the LDX group, and headache, irritability, epigastric discomfort, fatigue, influenza, malaise, nausea, sedation, somnolence, and upper abdominal pain in the ATX group [27]. In the placebo- and OROS-MPH-controlled study 325, the TEAEs leading to discontinuation were vomiting, anorexia, decreased appetite, angina pectoris, tachycardia, decreased weight, and insomnia in the LDX group, and decreased appetite, irritability, and insomnia in patients treated with OROS-MPH [25]. The case of angina pectoris was a 13-year-old boy who experienced pre-cardiac pain that was considered by the study investigator to be of moderate intensity and did not meet the criteria for a serious TEAE. During the study, this patient had no clinically significant laboratory abnormalities, no treatment or concomitant medications were reported, and all ECGs were normal [25]. No deaths were reported in any of the studies. Serious TEAEs (defined as those that resulted in death, were life threatening, required hospitalization or prolongation of hospitalization, resulted in persistent or significant disability or incapacity, caused congenital abnormality or birth defect, or were considered an important medical event) were reported in two studies. In study 303, there were two serious TEAEs in adults receiving LDX (leg injuries following an automobile accident and post-operative knee pain) but neither were judged to be related to study treatment [23]. Serious TEAEs reported in children and adolescents in study 325 were syncope, gastroesophageal reflux disease, and appendicitis in the LDX group; loss of consciousness, hematoma, and clavicle fracture in the placebo group; and syncope and overdose in the OROS-MPH group [25]. Of these, only the case of overdose in a patient receiving OROS-MPH was considered to be related to study drug. This patient inadvertently took two doses of OROS-MPH on the same day and experienced a non-serious episode of initial insomnia; the overdose was reported to be mild in severity, was resolved, and did not result in a change of dosage or treatment (data on file). It was a requirement of the study 325 protocol that all reported instances of syncope were classified as serious TEAEs, regardless of the intensity or medical significance of the event. As is typical for stimulant medications, LDX treatment was associated with small mean increases in blood pressure (BP) and pulse rate compared with placebo in all age groups, with the largest mean increases seen with LDX 70 mg (Table 2) [17, 23, 25–28]. LDX treatment was generally not associated with any clinically relevant changes in mean ECG parameters, including corrected QT interval, although clinically meaningful post-baseline ECG findings were observed at week 1 in two adolescent patients receiving LDX in one of the forced-dose studies (QT interval corrected by Fridericia’s formula [QTcF] of 479 and 413 ms, respectively), which led to study drug discontinuation; no other clinically concerning trends in ECG interval assessments were observed [26]. While mean changes in vital signs and ECG parameters were generally not considered to be clinically meaningful, as shown in Table 3, small numbers of patients in studies 317 (children and adolescents), 305 (adolescents), and 303 (adults) were reported to meet outlier criteria for various cardiovascular parameters at least once during the study, supporting the need for careful monitoring of patients during treatment [23, 26, 27, 31]. However, few patients met outlier criteria at more than two study time points (study 303) or at 2 consecutive weeks (study 305) (Table 3), suggesting that the cardiovascular effects of treatment were not sustained [26, 31]. Table 2 Table 2 Changes from baseline to endpoint in vital signs in randomized, parallel-group, double-blind clinical trials Table 3 Table 3 Published outlier analyses of changes in vital signs and electrocardiogram parameters in randomized, parallel-group, double-blind clinical trials Crossover and Open-Label Trials In addition to the double-blind, parallel-group trials described above, LDX has also been studied in four short-term, placebo-controlled, crossover studies (two in children, one in college students, and one in adults) and two short-term open-label studies (both in children) [18, 19, 32–35]. In all six trials, patients met Diagnostic and Statistical Manual of Mental Disorders, fourth revision, text revision (DSM-IV-TR) diagnostic criteria for ADHD. In study 201, children with ADHD (N = 52) received mixed AMP salts extended-release (MAS XR) for a 3-week dose-optimization period, followed by a 3-week, double-blind, crossover period, during which each individual received 1 week of treatment with placebo, 1 week with MAS XR (at the individually optimized dose), and 1 week with LDX (at a dose approximately equivalent to that of MAS XR by AMP base content); the order of treatments was randomized [32]. During the double-blind treatment period, the overall level of TEAEs was low and similar among patients receiving LDX (16 %), MAS XR (18 %), and placebo (15 %) [32]. The most frequent TEAEs (>2 % with any treatment) during the double-blind treatment period for patients receiving LDX, MAS XR, and placebo were insomnia (8, 2, 2 %, respectively), decreased appetite (6, 4, 0 %), anorexia (4, 0, 0 %), upper respiratory tract infection (2, 2, 0 %), upper abdominal pain (0, 4, 2 %), and vomiting (0, 2, 4 %). The second crossover trial in children (N = 117) was a 4-week open-label period, during which the dose of LDX was individually optimized, followed by a randomized, placebo-controlled, 2-way crossover phase (1 week each of LDX or placebo) [18]. The most frequent TEAEs (≥10 %) reported for LDX-treated patients (N = 129) during the 4-week dose-optimization period were decreased appetite (47 %), insomnia (27 %), headache (17 %), irritability (16 %), upper abdominal pain (16 %), and affect lability (10 %). In two short-term, open-label trials in children (7 weeks and 4–5 weeks in duration), the profile of TEAEs was similar to those seen in other studies of LDX and alternative stimulants [34, 35]. Again, the most frequent TEAEs were related to decreased appetite and trouble sleeping.

A 5-week, placebo-controlled, crossover study of LDX in 24 university students aged 18–23 years found the most frequent TEAEs were decreased appetite and trouble sleeping [33]. A second crossover trial in adults (aged 18–55 years; N = 142) consisted of a 4-week, open-label period, during which the dose of LDX was individually optimized to 30, 50, or 70 mg daily, followed by a randomized, placebo-controlled, 2-way crossover phase (1 week each of LDX or placebo) [19]. The most common TEAEs (≥10 %) during dose optimization were decreased appetite (52 %), dry mouth (43 %), headache (28 %), insomnia (26 %), upper respiratory tract infection (14 %), irritability (12 %), and nausea (11 %). During the crossover phase, no newly emergent TEAEs were reported in 5 % or more of adults receiving LDX, and the percentage of patients with any TEAE was lower for LDX-treated individuals (32 %) than those receiving placebo (42 %).
Safety and Tolerability in Long-Term Studies

The safety and tolerability of LDX over the long term (defined for the purposes of this paper as at least 6 months) has been evaluated in extension studies to four of the randomized, parallel-group, double-blind, placebo-controlled phase III trials described above [29, 30, 36, 37]. In each long-term extension study, patients received open-label, individually dose-optimized LDX (30, 50, or 70 mg taken once daily). The open-label treatment period lasted between 26 and 52 weeks in the study in children and adolescents (study 326) and 52 weeks in the other three long-term studies in children, adolescents, and adults (studies 302, 306, and 304, respectively).

The most common TEAEs reported in the long-term extension studies are shown in Table 4. These are largely similar to those reported in the short-term trials (Table 1), and are consistent with those reported for other stimulants. The overall rate of TEAEs did not differ greatly among age groups. As with the short-term trials, the most common TEAEs for LDX-treated patients across all age groups included decreased appetite (14–33 %), headache (17–21 %), and insomnia (12–20 %). Weight loss was more common in children and adolescents (16–18 %) than in adults (6 %). Anorexia was reported in 15 % of LDX-treated children and adolescents in study 326, but occurred in 5 % or less of patients receiving LDX in the other long-term studies.
Table 4
Table 4
Treatment-emergent adverse events reported in four long-term studies (≥6 months) of lisdexamfetamine dimesylate treatment [29, 30, 36, 37]

Most TEAEs reported in the long-term studies were mild or moderate in severity [29, 30, 36, 37]. Serious TEAEs and TEAEs leading to discontinuation were reported by 1–4 % and 6–16 % of patients receiving LDX, respectively (Table 4). The serious TEAEs reported in the long-term studies in children and in adults (studies 302 and 304) were judged by the study investigator to be unrelated to LDX treatment [29, 30]. In study 326 in children and adolescents, syncope and aggression (two cases of each) were the only serious TEAEs reported in more than one patient during the open-label LDX treatment period [36]. In this study, open-label treatment was followed by randomized treatment withdrawal; no clinically relevant safety signals were associated with the abrupt discontinuation of LDX [36]. In the long-term adolescent study (study 306), of the serious TEAEs, only three episodes of syncope were considered to be related to LDX treatment [37]. In this study, any new onset of syncope was considered an important medical event requiring reporting as a serious TEAE. TEAEs that led to treatment discontinuation included insomnia, aggression, irritability, decreased appetite, and depressed mood [29, 30, 37]. The mean changes in vital signs and corrected QT interval observed during the four extension studies were modest and consistent with the profile of LDX seen in the short-term trials (Table 5).
Table 5
Table 5
Changes from baseline to endpoint in vital signs and QTcF in four long-term studies (≥6 months) of lisdexamfetamine dimesylate treatment [29, 30, 36, 37]

The safety and efficacy of LDX has also been evaluated in a long-term maintenance-of-efficacy study in adults with ADHD (study 401) [38]. This study enrolled adults aged 18–55 years who had already received at least 6 months of treatment with commercially available LDX. During the initial phase of this study, patients received open-label treatment with their established commercial dose of LDX (30, 50, or 70 mg once daily) for 3 weeks. Of 122 patients who received open-label LDX, 20 % reported a TEAE; headache (2.5 %) and upper respiratory tract infection (2.5 %) were the only TEAEs with a frequency of greater than 2 %. As with study 326, no clinically relevant safety signals were associated with the randomized withdrawal of LDX treatment following open-label treatment in study 401 [36, 38].
Post-Marketing Safety Data

Published accounts of post-marketing data describing adverse events in patients receiving LDX are limited. Spiller at al. [39] described 28 patients who reported adverse events to one of five poison centers in the USA during the first 10 months of LDX marketing. In most (86 %) of these patients, the adverse reaction occurred within the first week of therapy, with agitation (43 %), tachycardia (39 %), insomnia (29 %), dystonia (29 %), vomiting (18 %), chest pain (14 %), hallucination (11 %), and jitters (11 %) occurring in more than 10 % of the patients. In addition, there are case reports of single instances of alopecia [40] and eosinophilic hepatitis [41] in patients with ADHD treated with LDX, and of chorea [42] and serotonin-like syndrome [43] following accidental ingestion of LDX.
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Specific Safety Concerns Associated with Stimulant Use
Weight and Growth

As with other stimulants, monitoring of height and weight in pediatric patients receiving LDX is recommended [21]. Reductions in weight and in expected height gains have been reported in multiple clinical trials assessing the use of stimulants for ADHD treatment; however, the relatively short duration of most studies has limited the available data on the long-term impact of stimulants on growth. A 3-year follow-up of the National Institute of Mental Health Multimodal Treatment Study of ADHD found that stimulant-treated children were shorter by an average of 2.0 cm and lighter by 2.7 kg after 3 years compared with un-medicated children [44]. However, the reductions in growth velocity were greatest in the first year of treatment, then decreased in the second year, and were absent in the third year when compared with un-medicated children.

To evaluate the effects of LDX treatment on growth in children, data were analysed from two North American, 4- to 6-week, short-term studies (studies 301 and 201) [24, 32] and a 52-week, long-term study in children (study 302, which enrolled patients from studies 301 and 201) [29]. In this analysis, the weight, height, and body mass index (BMI) of 281 children (aged 6–13 years) were assessed for up to 15 months and compared with norms from the US Centers for Disease Control (CDC) [45]. It was noted that, at baseline, patients were significantly taller and heavier than expected based on CDC norms. The mean (standard deviation [SD]) duration of LDX treatment was 265 (149) days. Consistent with the known effects of stimulants from other long-term studies [46], compared with expected changes based in CDC norms, gains in weight, height, and BMI in children receiving LDX were statistically significantly reduced, with the greatest rate of weight decrease observed within the first 6 months of treatment [45]. Across all studies, mean weight decreased by 0.2 kg, compared with an expected increase of 3.5 kg. Mean height increased by 3.9 cm, compared with an expected increase of 4.8 cm. Among children with endpoint data obtained at or beyond 12 months, the proportion of children with a BMI below or at the fifth percentile increased from 4 % at baseline to 15 % at endpoint. Growth was most affected in the heaviest and tallest children, for those who had not previously received stimulant treatment and for those with a greater cumulative exposure to LDX [45].

In the 7-week, phase III study in children and adolescents with ADHD (study 325), mean [SD] body weight decreased in the patients receiving LDX (−2.1 [1.9] kg) and OROS-MPH (−1.3 [1.4] kg), compared with an increase (+0.7 [1.0] kg) in patients receiving placebo [25]. Of the 47 patients (LDX, n = 35; OROS-MPH, n = 12) who had a potentially clinically significant decrease in weight at endpoint (≥7 % from baseline), three patients (LDX, n = 2; OROS-MPH, n = 1) moved from healthy weight BMI categories to underweight (defined as BMI less than the 5th percentile) [25]. In the short-term, forced-dose study in adolescents (study 305), the mean (SD) weight changes from baseline at week 4 were −3.0 (2.92), −4.5 (3.91), and −5.2 (3.20) lb for the 30, 50, and 70 mg/day LDX groups, respectively, and +2.3 (2.94) lb for the placebo group (this converts to approximately −1.36 [1.33], −2.05 [1.78], and −2.36 [1.45] kg for the 30, 50, and 70 mg/day LDX groups and +1.05 [1.34] kg in the placebo group). In adolescents receiving LDX 30, 50, and 70 mg for 52 weeks (study 306), mean (SD) changes in weight from baseline to endpoint were −0.1 (3.91), −0.4 (4.80), and −1.9 (6.08) kg, respectively [37]. Of the 171 patients with a healthy weight BMI at baseline, five were categorized as underweight at endpoint; there were no underweight individuals at baseline.

The effects of LDX on weight in adults and changes over the longer term are less certain. In the 52-week study 304 in adults, the mean change in weight from baseline to endpoint was −1.8 kg [30]. An increase in BMI was observed in the one adult who was underweight at baseline. Of the 105 adults with a normal BMI (18–24 kg/m2) at baseline, one patient ended the study as underweight (BMI 17.5 kg/m2 at endpoint) and six ended the study as overweight (BMI 24.0–25.1 kg/m2).
Sleep

ADHD itself may be associated with sleep disturbances, including difficulties in initiating sleep, reduced total sleep time, and poor sleep quality [47, 48]. The mechanisms by which this occurs are not well understood, and the impacts of comorbidities and ADHD medication on sleep remain unclear [47, 48]. Clinical guidelines provide recommendations for the management of sleep disturbance [49].

Sleep impairments, including insomnia, have been recorded as TEAEs in multiple clinical trials assessing the use of stimulants to treat ADHD, indicating that stimulant therapy may be the cause of sleep problems in some patients [50]. However, in a randomized, double-blind, placebo-controlled study in children, neither once-daily OROS-MPH nor transdermal MPH appeared to cause sleep problems or to exacerbate existing sleep impairments [51]. In addition, results from a 6-week, open-label study in 24 children with ADHD indicated that OROS-MPH treatment did not impair sleep and may even improve some aspects of sleep [52]. Kooij et al. [53] reported improved sleep quality in a small sample of adults with ADHD (N = 8) following 3 weeks of open-label stimulant therapy. Similarly, another study, which included 34 adults with ADHD, found that open-label treatment with MPH had beneficial effects on sleep compared with no treatment [54]. Insomnia was reported as a TEAE in 11–19 % of patients of all ages receiving LDX in short-term, randomized, placebo-controlled, parallel-group trials, compared with 0–5 % of patients receiving placebo (Table 1). In longer-term extension studies, the proportions of patients (12–20 %) receiving LDX who reported insomnia were similar to those observed in the short-term trials (Table 4).

In study 303 in adults (N = 420), mean global scores for the self-rated Pittsburgh Sleep Quality Index (PSQI) indicated that sleep quality at baseline was generally poor but did not differ between the treatment groups (LDX 5.8, placebo 6.3, p = 0.19). By week 4, least squares mean change from baseline in PSQI global score (where a decrease indicates an improvement in sleep quality) suggested that LDX was not associated with an overall worsening of sleep quality compared with placebo (LDX −0.8, placebo –0.5, p = 0.33), but was associated with improvement in the daytime functioning component compared with placebo (p = 0.0001) [55]. A post hoc analysis of this study examining categorical changes in PSQI found that similar proportions of adults receiving placebo and LDX shifted from good sleep (PSQI ≤5) at baseline to poor sleep (PSQI >5) at endpoint (8.2 and 7.7 %, respectively), while 8.2 % of the placebo group and 20.9 % of the LDX group had better sleep at endpoint than at baseline (p = 0.03, LDX vs. placebo) [56]. Thus, while reports of sleep-related TEAEs are elevated in patients receiving LDX compared with placebo, these findings are not reflected in impaired sleep quality in adults with ADHD as measured by the PSQI [56].

Polysomnography and actigraphy parameters were examined in 24 children (aged 6–12 years) with ADHD before and after treatment with LDX in a randomized, placebo-controlled, double-blind, parallel-group study [57]. There was no statistically significant increase in latency to persistent sleep in patients treated with LDX compared with the placebo group. Furthermore, there were no significant differences between LDX and placebo in actigraphy and secondary polysomnography measures. However, the number of awakenings after sleep onset significantly decreased from 7.9 at baseline to 3.3 at week 7 in the LDX treatment group (p < 0.0001 compared with baseline). However, owing to the small sample size and exploratory nature of this pilot study, these results should be interpreted with caution. Overall, the impact of stimulants on sleep in patients with ADHD is unclear. The heterogeneity of observations across studies may reflect differences in the class of drug, formulation, and dose-scheduling protocols [49]. Intuitively, a stimulant with a duration of action lasting into the evening following a single morning dose might be expected to be associated with sleep-related TEAEs yet, paradoxically, patients receiving shorter-acting formulations may experience sleep disturbances due to a rebound effect in the evening after their medication wears off [49]. Abuse Potential Like other stimulants, LDX is a controlled substance with the potential for non-medical use (NMU) and diversion [21]. Several pharmacokinetic and physicochemical characteristics of LDX may lower the potential for abuse, misuse, or diversion compared with immediate-release stimulant formulations. First, in common with all long-acting stimulants, once-daily dosing makes parental supervision easier to enforce [5]. Second, the maximum plasma concentration of d-AMP is reached approximately 3.5 h after a single dose of LDX in children with ADHD, with an elimination half-life ranging from 8.61 to 8.90 h [16]. The ‘high’ associated with stimulants is dependent on a rapid rise in stimulant concentration and the resultant increase in monoamine receptor occupancy [58]. Accordingly, the absence of an early sharp rise and spike in systemic d-AMP concentrations following LDX administration may result in a lower abuse potential compared with immediate-release AMP formulations [59]. Third, the requirement for LDX to be converted to d-AMP via rate-limited hydrolysis in the blood means that opening LDX capsules, or dissolving the contents in water, will not yield the active ingredient d-AMP for direct administration [59]. Finally, a randomized, crossover study in healthy men suggested that switching between oral and intranasal routes of administration of LDX does not markedly modify d-AMP plasma concentration–time profiles [60]. Drug-liking scores for LDX were assessed in two phase I studies in adult volunteers with a history of stimulant abuse. These studies found that drug-liking scores for oral (100 mg) and intravenous (25 and 50 mg) LDX were not significantly different from placebo and were lower than those for equivalent doses of immediate-release d-AMP [59, 61]. The lower drug-liking of LDX compared with d-AMP at equivalent doses are presumably due to the delayed pharmacodynamic properties of the former that result from the prodrug nature. At the supra-therapeutic oral dose of 150 mg, the drug-liking score for LDX was similar to that of 40 mg d-AMP, despite a 50 % greater AMP free-base content in the former compared with the latter, and drug-disliking scores were higher [59]. While these results are suggestive of a lower potential for the abuse of LDX than d-AMP, it should be noted that the studies enrolled small numbers of individuals who received LDX for short periods of time under controlled conditions. Large-scale, post-marketing data relevant to the abuse-liability of LDX are beginning to emerge. An internet survey of 10,000 US adults (aged 18–49 years) reported lifetime NMU of pain medications, sedatives/tranquilizers, sleep medications, and prescription stimulants to be 24.6, 15.6, 9.9, and 8.1 %, respectively. Within prescription stimulants, product-specific rates of NMU (per 100,000 prescriptions dispensed) were generally low but highest for immediate-release formulations (Ritalin®, 1.62; Adderall®, 1.61) compared with longer-acting preparations (Adderall XR® 0.62, Concerta® 0.19, LDX 0.13) [62]. The most commonly reported motivation for stimulant NMU in this study were ‘increasing alertness’ (33–61 %) and ‘enhancing academic or work performance’ (39–57 %) rather than ‘getting high’ (20–30 %) [62]. A second evaluation of the NMU of prescription ADHD stimulants among adults was based on 147,816 assessments from the National Addictions Vigilance Intervention and Prevention Program (NAVIPPRO) system. NMU, over the previous 30 days, of prescription stimulants (1.29 %) was lower than for opioids (19.79 %) and sedatives (10.62 %). Again, NMU of stimulant products was low: Ritalin®, 0.16; Adderall® 0.62; Adderall XR®, 0.42; Concerta®, 0.08; LDX 0.12) [63]. A cross-sectional, population-based US survey, which included 443,041 respondents from the 2002–2009 National Survey on Drug Use and Health, found that lifetime NMU of prescription ADHD stimulants was reported by 3.4 % of respondents aged 12 years or older, most of whom had already been engaged in the abuse of an illicit drug or NMU of another prescription drug [64]. In addition, data from the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS®) System, a US national surveillance system that monitors the abuse, misuse, and diversion of prescription controlled substances, indicated that RADARS System Poison Center call rates and RADARS System Drug Diversion rates for prescription stimulants were low and that rates for extended-release AMP formulations, including LDX, were similar to those for extended-release MPH (from third quarter of 2007 to second quarter of 2011) [65]. Cardiovascular Safety Case reports of sudden death in stimulant-treated patients, combined with the sympathomimetic properties of this class of drug, led European and North American treatment guidelines to recommend that clinicians be aware of any cardiovascular risks that may affect a patient’s suitability for ADHD medication [1, 2, 6, 66]. Thus, prescribing information for LDX warns of the risk of serious cardiovascular reactions, including sudden death, and recommends that its use is avoided in patients with cardiac abnormalities, cardiomyopathy, serious heart arrhythmia, or coronary artery disease [21]. Furthermore, the checking of fingers and toes for circulation problems (peripheral vasculopathy, including Raynaud’s phenomenon) has recently become a requirement for patients receiving stimulants, including LDX, for the treatment of ADHD [21]. However, most large-scale epidemiological studies and randomized, controlled trials have failed to substantiate concerns of elevated cardiovascular risk of ADHD medications [67–69]. Of a series of five retrospective, administrative claims-based US studies in children and adolescents, the two smallest studies did report a slightly increased risk of emergency department visits attributed to cardiac symptoms such as tachycardia or palpitations, but the three largest studies, each comprising more than a million patients, found no association between stimulants and composite endpoints of sudden cardiac death, myocardial infarction, stroke, and ventricular arrhythmia [68]. Similarly, a retrospective study that examined the UK General Practice Research Database found no increased risk of sudden death associated with ADHD medications (stimulants or ATX) in a population of 18,637 aged 2–21 years [70]. Although background rates of serious cardiovascular events in children and adolescents are small [68], evidence of an increased risk of serious cardiac events in adult patients receiving ADHD medications is also limited. A retrospective US study of healthcare records of 443,198 adults aged 25–64 years (150,359 of whom received ADHD medications) found no evidence of sudden cardiac death, myocardial infarction, or stroke associated with the use of ADHD medication compared with no use [71]. Finally, a recent retrospective study of Medicaid and commercial US databases of 43,999 adult (≥18 years of age) new MPH users and 175,955 matched non-users found a small increased risk of sudden death or ventricular arrhythmia (but not stroke, myocardial infarction, or combined stroke/myocardial infarction) among MPH users, although the lack of a dose-response effect argued against a causal relationship [72]. Cardiovascular-related serious TEAEs and discontinuations, and ECG abnormalities, were rare in clinical trials of LDX. In short-term double-blind, randomized, controlled, phase III trials in patients with ADHD of all ages, LDX was associated with modest increases in systolic and diastolic BP and pulse rate [23–27]. Outlier data reported for study 317 in children and adolescents indicated that 15.0 % of patients receiving LDX had a pulse rate ≥100 bpm compared with 24.2 % of patients receiving ATX at some point during the study. In this study, similar proportions of children receiving LDX and ATX experienced systolic BP (SBP) ≥120 mmHg (LDX 12.8 %, ATX 11.2 %) or diastolic BP (DBP) >80 mmHg (LDX 11.7 %, ATX 13.3 %), and similar proportions of adolescents experienced SBP ≥130 mmHg (LDX 6.1 %, ATX 8.8 %) or DBP >80 mmHg (LDX 21.2 %, ATX 17.6 %). There were no cases of QTcF interval ≥450 ms [27]. In study 305 in adolescents, 3.0 % of patients receiving LDX had a heart rate ≥100 bpm at endpoint compared with none receiving placebo. No participants had a QTcF interval of ≥480 ms [26]. Post hoc analyses of cardiovascular parameters in adults (study 303) found that the proportions of patients who experienced a pulse rate of ≥100 bpm during treatment with LDX ranged from 3.3 % for the 70-mg dose to 8.5 % for the 50-mg dose; no patients in the placebo group exceeded this threshold [31]. There were no clinically meaningful ECG abnormalities [23]. Modest increases in cardiovascular vital signs were also reported during the crossover phase of a placebo-controlled classroom study in children (aged 6–12) with ADHD in both LDX and placebo groups [18]. Maximum mean (SD) increases in pulse rate, SBP, and DBP (9.9 [9.8] bpm, 4.2 [9.2] mmHg, and 4.7 (8.5) mmHg, respectively) were all observed in the LDX 70-mg group. Finally, a small (N = 28), 4- to 5-week, single-blind, modified laboratory school study in children (aged 6–12 years) with ADHD reported one case each of tachycardia, BP >95th percentile of normal range (both occurred once only), and a prolongation of QTc (461 ms, which resolved at medication discontinuation and did not reappear at the resumption of treatment) in patients receiving LDX [73].

In the short-term, randomized, double-blind trial in children (study 301), ECG voltage criteria for ventricular hypertrophy led to discontinuation of at least 1 % of patients receiving LDX [21], although subsequent analysis of these data suggested that minor variations in ECG interpretation contributed to these discontinuations (data on file). To assess the impact of LDX treatment on cardiovascular and cardiopulmonary structure and function using comprehensive provocative physiological testing, a prospective open-label study was conducted in 15 adults with ADHD [74]. Participants were treated with LDX for up to 6 months and underwent transthoracic echocardiography and cardiopulmonary exercise testing. This study found no clinically meaningful changes in cardiac structure and function, or in metabolic and ventilatory variables at maximum exertion. However, the authors acknowledged that, while their results are generally reassuring, these findings were limited by the small sample size and uncontrolled nature of the study design.
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Caveats of Reported Lisdexamfetamine Dimesylate (LDX) Safety Outcomes

The interpretation of safety and tolerability data from the LDX clinical trial program requires that several limitations be considered. First, the relatively small number of patients enrolled in clinical trials of relatively short duration means that rare TEAEs, or TEAEs that emerge only after extended treatment, are unlikely to be detected. Second, it is important to note that individuals with comorbid psychiatric disorders, extremes of weight, or major neurological and cardiovascular conditions were excluded from the clinical trials, and all patients were in generally good health. Third, is the tendency for long-term studies in particular to self-select for responders. Thus, it is unlikely that these phase III clinical trials of LDX reflect the full spectrum of patients seen in clinical practice. Finally, it should be acknowledged that all of the clinical trials described were sponsored by the manufacturer of LDX.

Post-marketing surveillance can provide additional information regarding drug safety in clinical practice and TEAEs reported in patients treated with LDX during the post-marketing period [21]. However, these data rely on voluntary reporting of TEAEs from a population of uncertain size, making it difficult to estimate the frequency of events or to establish a causal relationship to drug exposure reliably [21]. The EU-based, Attention Deficit Drugs Use Chronic Effects (ADDUCE) Consortium has been established, at the request of the European Medicines Agency and with European Union FP7 funding, in response to the lack of knowledge regarding the long-term effects of stimulants [75]. Initially focusing on MPH treatment, the ADDUCE project plans to perform a series of pharmacovigilance investigations into the long-term effects of stimulants on growth, the neurological system, psychiatric states, and the cardiovascular system, and it is hoped that new research tools developed during this process can then be applied to other ADHD medications, including LDX. With the exception of LDX misuse mentioned earlier, published large-scale, post-marketing data on LDX are currently limited. However, a company-sponsored phase IV, open-label study (study 404) is underway and will provide information regarding the safety profile of LDX in children and adolescents with ADHD over a 2-year treatment period.
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Conclusions

Results from clinical trials of LDX indicate that this once-daily, long-acting prodrug stimulant has a safety and tolerability profile similar to that of other stimulants. The TEAEs reported most commonly in children, adolescents, and adults include decreased appetite and insomnia. Most TEAEs are mild to moderate in severity. Due to the sympathomimetic effects of LDX, small mean increases in blood pressure and pulse rate can occur. These changes alone would not be expected to have short-term consequences, but all patients receiving LDX should be monitored for larger changes in blood pressure and pulse rate, and LDX should not be used in patients with serious cardiac problems. As a result of its prodrug formulation, there is low intra- and inter-patient variability in the systemic exposure to d-AMP, which may help facilitate LDX dose optimization. The prodrug formulation of LDX may also lead to reduced abuse potential of LDX compared with immediate-release d-AMP. Overall, the choice of medication for patients with ADHD should be based on the benefit–risk ratio for each individual.
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Acknowledgments

The authors thank Drs Elizabeth Gandhi and Eric Southam of Oxford PharmaGenesis™ who provided editorial support funded by Shire, including collating the comments of the authors and editing the manuscript for submission.
Disclosures

LDX is manufactured and marketed by Shire. B Caballero, S Sorooshian, and R Civil are employees of Shire and own stock/stock options. DR Coghill has received compensation for serving as a consultant or speaker; or has, or the institutions he works for have, received research support or royalties from the following companies or organizations: Flynn Pharma, Janssen-Cilag, Lilly, Medice, Novartis, Otsuka, Oxford University Press, Pfizer, Schering-Plough, Shire, UCB, Vifor Pharma.
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31. Adler LA, Weisler RH, Goodman DW, Hamdani M, Niebler GE. Short-term effects of lisdexamfetamine dimesylate on cardiovascular parameters in a 4-week clinical trial in adults with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2009;70(12):1652–1661. doi: 10.4088/JCP.09m05335pur. [PubMed] [Cross Ref]
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35. Wigal SB, Wong AA, Jun A, Stehli A, Steinberg-Epstein R, Lerner MA. Adverse events in medication treatment-naive children with attention-deficit/hyperactivity disorder: results from a small, controlled trial of lisdexamfetamine dimesylate. J Child Adolesc Psychopharmacol. 2012;22(2):149–156. doi: 10.1089/cap.2010.0095. [PubMed] [Cross Ref]
36. Coghill D, Banaschewski T, Lecendreux M, et al. Maintenance of efficacy of lisdexamfetamine dimesylate in children and adolescents with attention-deficit/hyperactivity disorder: randomized withdrawal design. Poster presented at the EUNETHYDIS 2nd international ADHD conference, Barcelona; 2012. http://www.shirecongressposters.com/247852. Accessed 18 June 2013.
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39. Spiller HA, Griffith JR, Anderson DL, Weber JA, Aleguas A. Poison centers detect an unexpectedly frequent number of adverse drug reactions to lisdexamfetamine. Ann Pharmacother. 2008;42(7):1142–1143. doi: 10.1345/aph.1L240. [PubMed] [Cross Ref]
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46. Faraone SV, Biederman J, Morley CP, Spencer TJ. Effect of stimulants on height and weight: a review of the literature. J Am Acad Child Adolesc Psychiatry. 2008;47(9):994–1009. [PubMed]
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Articles from Springer Open Choice are provided here courtesy of Springer

Lisdexamfetamine Dimesylate
The First Prodrug Stimulant
David W. Goodman, MDcorresponding author
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This article has been cited by other articles in PMC.
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Abstract

Attention deficit hyperactivity disorder (ADHD) is one of the most common neurobehavioral disorders affecting children. The symptoms often persist into adolescence and adulthood, causing significant impairments. ADHD often remains undiagnosed and untreated, and because of its potential long-term impact, recognition, diagnosis, and management in children have become increasingly important. Education about ADHD and the available therapy options is important for both the patient and the caregiver to achieve more effective treatment. Efficacy and safety data on stimulant medications have provided evidence for their effectiveness in treating ADHD. Although they remain the first-line treatment, the need for multiple daily dosing and concerns about the general risk profile of stimulants have led to the development of new agents, including once-daily formulations that provide prolonged duration of action. However, pharmacokinetic variability of these formulations can result in inconsistent effects in some patients. The use of prodrug technology and the development of the only prodrug stimulant, lisdexamfetamine dimesylate (LDX), provide a promising treatment option for ADHD with an improved overdose potential risk profile when compared to d-amphetamine. This review of LDX, which presents the efficacy, safety, and pharmacokinetic profile of this new class of stimulant, is designed to help the physician better understand the clinical use of this agent in treating ADHD.
Keywords: ADHD, stimulant medications, prodrugs, lisdexamfetamine dimesylate, Vyvanse
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Introduction

Attention deficit hyperactivity disorder (ADHD) is one of the most common behavioral disorders in childhood, estimated to occur worldwide in as many as eight percent to 12 percent of children.1 Childhood ADHD persists into adolescence and adulthood in an estimated 10 percent to 70 percent of cases,2–4 with impairing symptoms experienced by at least 50 percent of these patients.1 A US epidemiologic adult ADHD study reported a prevalence of 4.4 percent, yet only a small fraction of adults with ADHD (10.9%) had received treatment prior to the survey.5

Stimulants have the most evidence for efficacy and safety for the treatment of ADHD and remain the first-line therapy for ADHD.6 Concerns about the general risk profile of stimulant medications in clinical practice are common, including the association between ADHD and substance use disorder.7 Tampering, including mechanical manipulation, of some formulations has allowed misuse through administration via intended or non-intended routes and has led to the need for the development of new agents,8 including nonstimulants, developed as nonabusable alternatives for ADHD.

Since 2000, once-daily, modified-release stimulant formulations that provide prolonged delivery have been developed for the treatment of ADHD.9 While it is not known if this pharmacokinetic variability contributes to therapeutic duration variability, formulations with less pharmacokinetic variability may provide more consistent clinical results.10 More recently, development of long-acting formulations has included a prodrug stimulant representing a new class of agents for the treatment of ADHD that has less pharmacokinetic variability and the potential to produce more consistent clinical effects and less abuse potential.
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Prodrugs: a New Class of Stimulants for the Treatment of ADHD

The concept of prodrugs as a useful formulation was proposed as early as 1958 by Adrien Albert, who described the alteration of the physiochemical properties of drugs to render them pharmacologically inactive until metabolized in the body to the active drug moiety.11 By definition, a prodrug is a compound that undergoes biotransformation before exhibiting its therapeutic effect.12,13 Some therapeutically effective prodrugs include the oral fluoropyrimidine chemotherapy agents, capecitabine and uracil, prodrugs of 5-fluorouracil, and the thienopyridine antiplatelet agents, ticlopidine and clopidogrel.

Lisdexamfetamine dimesylate (LDX, Vyvanse™; Shire US Inc.) is the only prodrug stimulant and is indicated for the treatment of ADHD in children aged 6 to 12 years. LDX is a therapeutically inactive molecule; after oral ingestion, it is converted to l-lysine, a naturally occurring essential amino acid, and active d-amphetamine, which is responsible for the drug’s activity. LDX is unlike other long-acting stimulants in that it is not an encapsulated matrix or a bead formulation, but instead has extended-release characteristics because it is a prodrug.9 LDX was developed with the goal of providing once-daily treatment with an extended duration of effect that is consistent throughout the day, with a reduced potential for abuse, overdose toxicity, and drug tampering.
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Solubility and Pharmacokinetic Studies of Lisdexamfetamine Dimesylate

In-vitro study. The pH solubility profile of LDX in saturated buffered aqueous solutions (pH 1–13) was determined by a high-pressure liquid chromatography assay that was specific for LDX. Within a physiologically relevant pH range (pH 1–8), the solubility profile of LDX was not affected by the pH of the solution, and increasing the pH from 8 to 13 resulted only in modest reductions in LDX solubility.14 The results suggest that the conversion of LDX to d-amphetamine should not be affected by gastrointestinal pH. Therefore, alkalinizing agents, such as sodium bicarbonate or other antacids, should not affect the absorption of LDX. Because LDX is a prodrug that is rapidly absorbed from the gastrointestinal tract and converted to d-amphetamine, it is not a controlled-release delivery vehicle and is unlikely to be affected by alterations in normal gastrointestinal transit times.

Phase I study. The pharmacokinetic profile of the LDX formulation was determined in a phase I, open-label, randomized, single-dose, three-treatment, three-period, crossover study.14,15 This comprised three 1-week study periods with 7-day washout between doses. Eighteen healthy volunteers (9 males, 9 females) aged 18 to 55 years received a single LDX dose of 70mg under three dose conditions: (1) fasting and with capsule only; (2) solution containing capsule contents; and (3) intact capsule after a high-fat meal. The analysis showed that when LDX was administered in solution or as an intact capsule with or without food, d-amphetamine systemic exposure bioavailability was equivalent for all dosing conditions as evidenced by AUC and Cmax values. However, significant differences in tmax values (mean hours±SD) were seen between the fasted (3.8 ± 1.0) and fed (4.7 ± 1.1) conditions (p<0.001). Overall, these results demonstrated that LDX may be taken with or without food or dissolved in water and immediately consumed, without affecting the overall extent of absorption. Phase II study. The inter-subject (patient to patient) pharmacokinetic variability of d-amphetamine after oral administration of LDX and mixed amphetamine salts (MAS XR; Adderall XR®) was determined in a phase II study.16 Previous pharmacokinetic studies of MAS XR in healthy volunteers have shown considerable inter-subject variability in serum plasma d-amphetamine levels (Cmax) over time.10 This randomized, multicenter, double-blind, three-treatment, three-period, crossover study included children aged 6 to 12 years with a primary diagnosis of ADHD as defined by Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria.17 As a secondary trial objective, pharmacokinetic data were reported at the last visit for the largest patient cohort, eight patients who received 70mg/day of LDX and nine patients who received 30mg/day of MAS XR (equivalent d-amphetamine base doses) for one week. Levels of d-amphetamine reached median tmax in 4.5 hours (mean 5.1, range 4.5–6) for LDX and 6.0 hours (mean 6.6, range 3–12) for MAS XR (Table 1).16 Corresponding percent coefficients of variation were 15.3 percent and 52.8 percent, respectively, meaning that the tmax is 3.5 times less variable with LDX than MAS XR. Mean (± SD) maximum plasma concentrations (Cmax) were 155±31.4ng/mL for LDX and 119±52.5ng/mL for MAS XR. Corresponding coefficients of variation were 20.3 percent and 44.0 percent, respectively. Release of d-amphetamine was more predictable after oral administration of 70mg of LDX than 30mg of MAS XR as measured by tmax and Cmax. Overall, LDX demonstrated low inter-subject variability of pharmacokinetic measures with consistent exposure to d-amphetamine.16 Table 1 Table 1 Pharmacokinetics of d-amphetamine after oral administration of 70mg/day of LDX or 30mg of MAS XR Go to: Efficacy Studies With Lisdexamfetamine Dimesylate The efficacy and safety of LDX for the treatment of ADHD were established on the basis of results from two controlled clinical trials in children aged 6 to 12 years who met DSM-IV criteria for ADHD.18–20 Phase II study. Biederman and Boellner, et al., recently conducted a multicenter, double-blind, placebo-controlled, crossover-design, analog-classroom study in 52 children with ADHD aged 6 to 12 years (mean, 9.1±1.7 years).18,20 After three weeks of open-label dose adjustment and optimization with 10, 20, or 30mg/day of MAS XR, subjects were randomly assigned in a crossover design to treatment with the same doses of MAS XR; equivalent LDX doses of 30, 50, and 70mg/day, respectively; or placebo once daily for one week. Efficacy was assessed by means of the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Deportment Rating Scale, the Permanent Product Measure of Performance (PERMP) scale, and the Clinical Global Impressions-Improvement (CGI-I) scale. For each measure of efficacy (SKAMP, PERMP, and CGI-I scales), similar improvements were seen in children receiving LDX and MAS XR at each time point over 12 hours, and each treatment was significantly better at all doses than placebo (p<0.0001). On the CGI-I, ratings of very much improved or much improved were seen in 74 percent of subjects who received LDX and 72 percent of those who received MAS XR, compared with 18 percent of subjects receiving placebo (Figure 1). Thirty-two percent of subjects who received LDX were rated very much improved compared with 16 percent of subjects who received MAS XR and two percent of subjects who received placebo. Adverse events (AEs) were reported by 29 of the 52 subjects during the study. The most common AEs reported with MAS XR during the open-label, dose-titration phase were headache (15%), decreased appetite (14%), and insomnia (10%). During the double-blind phase, 16 percent of LDX-treated subjects, 18 percent of MAS XR-treated subjects, and 15 percent of placebo-treated subjects reported AEs. AEs that occurred during the double-blind phase with an incidence rate of ≤2 percent were insomnia (8%), decreased appetite (6%), and anorexia (4%) in LDX-treated subjects; decreased appetite (4%), upper abdominal pain (4%), vomiting (2%), and insomnia (2%) in MAS XR-treated subjects; and vomiting (4%), insomnia (2%), and upper abdominal pain (2%) in placebo-treated subjects. No serious AEs were reported. Figures 1 Figures 1 Clinical Global Impressions Scale - Mean improvement at assessment from baseline for intent-to-treat population who received placebo, LDX, or MAS XR.18,20 Phase III study. Biederman, et al., also conducted a double-blind, multicenter, placebo-controlled, parallel-group study in 290 children (201 boys and 89 girls) aged 6 to 12 years (mean, 9±1.8 years) with a primary diagnosis of ADHD.19 The children were randomly assigned to fixed-dose treatments consisting of oral doses of 30, 50, or 70mg/day of LDX or placebo once daily each morning for four weeks. A forced-dose design was employed for LDX treatments to assess the efficacy and tolerability of each individual dose as follows: 30mg for four weeks, 50mg (30mg/day for Week 1, with forced-dose escalation to 50mg/day for Weeks 2–4), or 70mg (30mg/day for Week 1, with forced-dose escalation to 50mg/day for Week 2 and 70mg/day for Weeks 3 and 4). Efficacy was assessed using the parent- and investigator-completed ADHD Rating Scale (ADHD-RS), the CGI-I, and the Conners Parent Rating Scale (CPRS). Of the 290 randomized patients, 230 completed the study (56 patients received LDX 30mg, 60 patients received LDX 50mg, 60 patients received LDX 70mg, and 54 patients received placebo). Significantly greater improvements in ADHD-RS total scores (mean change from baseline to endpoint) were seen with each of the three LDX doses compared with placebo (p<0.001 for all comparisons). Based on ADHD-RS scores at treatment endpoint, the effect sizes were 1.21, 1.34, and 1.60 in the 30-, 50-, and 70-mg groups, respectively, determined by the corresponding between-group differences. Throughout the study, assessment of symptomatic behaviors of ADHD using the CPRS in the morning (~10 AM), afternoon (~2 PM), and evening (~6 PM) showed significantly greater improvements (p<0.01) in symptom control throughout the day in each LDX dose group than in patients who received placebo. CGI-I scores were significantly improved (p<0.0001) with all three doses of LDX compared with placebo; ratings of very much improved or much improved were seen in ≤70 percent of patients in the LDX treatment groups compared with 18 percent of patients who received placebo. Overall, AEs in patients who received LDX were typical of amphetamine products.19 The most frequently reported AEs among patients receiving LDX compared with placebo were decreased appetite (39% vs. 4%), insomnia (19% vs. 3%), upper abdominal pain (12% vs. 6%), headache (12% vs. 10%), irritability (10% vs. 0%), vomiting (9% vs. 4%), weight decrease (9% vs. 1%), and nausea (6% vs. 3%). Most AEs were mild to moderate and occurred in the first week of treatment. Treatment with LDX was not associated with statistically significant changes in laboratory values, mean electrocardiogram (ECG) values (including corrected QT intervals), and systolic or diastolic blood pressure measures.21 There was a statistically significant change in pulse relative to placebo at endpoint, with each active treatment group showing an increase from baseline. The least-squares mean differences versus placebo in pulse rate from baseline to endpoint were 0.3±1.2 bpm for the LDX 30mg group (baseline pulse 82.2 bpm), 2.0±1.2 bpm for the 50mg group (baseline pulse 81.7 bpm), and 4.1±1.2 bpm for the 70mg group (baseline pulse 82.8 bpm) (p=0.0224, ANCOVA). No statistically significant changes from baseline were seen for any individual treatment week. Observed changes were not clinically meaningful and were consistent with results seen with other stimulant agents. Long-term efficacy and safety of LDX-phase III study. A 12-month, open-label, single-arm study was conducted to determine the long-term efficacy and safety of LDX in children.22 The intent-to-treat population consisted of 189 boys and 83 girls aged 6 to 12 years (mean, 9.2 years) with DSM-IV diagnosis for ADHD. Subjects were previously enrolled in a double-blind clinical study and may or may not have received prior treatment with LDX, except for one subject who was newly enrolled. After a one-week washout period, all subjects were started on 30mg/day of LDX and either maintained on this dose or titrated by the investigator to a dose of 50 or 70mg/day over a four-week period, based on effectiveness and tolerability. Treatment was maintained for up to 11 more months during which the doses could be changed for optimal effectiveness and tolerability; however, most of the dose changes occurred early in the study, suggesting that tolerance to medication did not occur. Efficacy was assessed using the ADHD-RS scores at endpoint and from baseline over the course of treatment, and the CGI-I scale.22 At endpoint (last observation), there was significant improvement (>60%, p<0.0001) in ADHD-RS total scores compared with baseline. Beginning at week 4, reductions in ADHD-RS total scores occurred and were seen throughout the 12-month treatment period. Using a clinician-completed rating scale (CGI), more than 80 percent of the patients were rated as much improved or very much improved by study endpoint. Additionally, more than 95 percent of those who completed 12 months of treatment were improved. LDX was generally well tolerated, with most of the treatment-related AEs occurring during the first eight weeks of treatment. AEs reported in 10 percent or more of the patients included decreased appetite, weight decrease, headache, insomnia, upper abdominal pain, upper respiratory infection, nasopharyngitis, and irritability. During the second eight weeks of treatment, only decreased appetite and weight decrease occurred in more than five percent of subjects. No statistically or clinically significant changes in ECG values or blood pressure were seen over the study period.23 The mean changes from baseline were 0.3 to 3.5 bpm for pulse; -1.8 to 1.0mmHg for systolic blood pressure; and -1.0 to 0.7mmHg for diastolic blood pressure. The mean increases from baseline in heart rate ranged from 1.8 to 5.2 bpm. Mean changes in QT/QTc intervals ranged from -4.7 to -1.8msec for QT, -0.4 to 2.2msec for QTc-F, and 1.1 to 6.4 msec for QTc-B. Twenty five (9%) of the 272 LDX-treated subjects discontinued treatment because of AEs, including three for decreased appetite, three for irritability, three for aggression, two for anxiety, and two for decreased weight. There were no discontinuations related to ECG findings. Go to: Abuse Liability Data LDX is the only product for the treatment of ADHD that includes abuse liability data in the product label. Support for the reduced abuse potential of LDX relative to immediate-release d-amphetamine has been shown in two abuse liability studies in human subjects.24,25 The abuse potential of oral LDX and d-amphetamine was compared in 38 adult non-ADHD subjects who had a history of stimulant abuse.24 In the double-blind, placebo-controlled, crossover study, oral doses of 50mg, 100mg (equivalent to 40mg of d-amphetamine), and 150mg of LDX and 40mg of d-amphetamine sulfate were administered. For the primary measure of subjective responses on a scale of the drug-liking effects, the Drug Rating Questionnaire-Subject (DRQS) Liking Scale, the maximum post-dose change in score from baseline was significantly greater in the subjects who received d-amphetamine 40mg than the equivalent 100-mg dose of LDX (p<0.05) when compared to placebo. Mean drug-liking scores peaked between 1.5 and 2 hours post-dose in subjects who received d-amphetamine and between 3 and 4 hours post-dose in subjects who received LDX, in keeping with the slower rise in LDX blood level. At a higher dose of LDX (150mg; equivalent to 1.5 times the dose of d-amphetamine used in this study), the maximum drug-liking score was similar to that after 40mg of d-amphetamine; however, the peak effect of LDX was two hours later than that of d-amphetamine, reflecting a slow ascent in serum level. In the second double-blind crossover study, equivalent intravenous doses of 50mg of LDX and 20mg of d-amphetamine were administered over a two-minute period at 48-hour intervals to nine adult non-ADHD subjects who had a history of drug abuse.25 Intravenous LDX at doses of 50mg did not produce significantly different liking scores as measured by the DRQS Liking Scale compared with placebo (p=0.29). In contrast, equivalent doses of 20mg of intravenous d-amphetamine did have significantly more liking effects than placebo (p=0.01). Mean peak behavioral and subjective effects were observed at 15 minutes post-dosing for d-amphetamine and between 1 and 3 hours for LDX. Go to: Conclusion Recognition, diagnosis, and management of ADHD in children have become increasingly important in the primary care setting. Stimulants remain the first-line treatment for ADHD, but the need for multiple daily dosing can be problematic for some patients when using short-acting stimulants. Concerns about the general risk profile of stimulant medications have led to the need for the development of new agents, including once-daily stimulant formulations that provide a prolonged duration of action and may have a reduced potential for risk of abuse. Although long-acting formulations have been shown to be effective in treating ADHD, pharmacokinetic variability can theoretically result in inconsistent duration of action across patients. The recent development and approval of LDX, the only prodrug stimulant, represents a new class of agents for the treatment of ADHD. Clinical evidence supports the effectiveness of LDX in the treatment of children with ADHD, while exhibiting reduced pharmacokinetic variability in maximum concentration and time to maximum concentration, and a tolerability profile similar to that of other long-acting stimulants. LDX has been shown to provide significant symptom control throughout the day for children with ADHD. In human abuse liability studies, LDX produced lower subjective responses on a test of drug-liking effects than dose-equivalent immediate-release d-amphetamine. In human abuse liability studies with oral and intravenous administration, LDX produced lower subjective responses on a test of drug-liking effects in adult substance abusers compared to dose-equivalent immediate-release d-amphetamine.24,25 The reduced drug-likability is a unique attribute of LDX relative to other stimulant preparations and is cited in the prescribing information.26 Go to: Acknowledgments I thank the staff of Excerpta Medica, Bridgewater, New Jersey, for their assistance in the preparation of this manuscript. Go to: References 1. Biederman J, Faraone SV. Attention-deficit hyperactivity disorder. Lancet. 2005;366:237–48. [PubMed] 2. Spencer TJ, Adler LA, McGough JJ, et al. and The Adult ADHD Research Group. Efficacy and safety of dexmethylphenidate extended-release capsules in adults with attention-deficit/hyperactivity disorder. Biol Psychiatry. 2007;61:1380–7. [PubMed] 3. McGough JJ, Barkley RA. 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