2008 - paliperidone extended-release tablets for the acute and maintenance treatment of...

7/29/2019 2008 - Paliperidone Extended-release Tablets for the Acute and Maintenance Treatment of Schizophrenia

1/18

C lin ic al T h e r a p e u t i c s /V o l u m e 3 0 , N u m b e r 2 , 2 0 0 8

N ew D r ugPaliperidone Extended-Release Tablets for the Acute andMaintenance Treatment of SchizophreniaJill A. Fow ler, Pharm D; Tawny L. Bettinger, Ph arm D , BCPP; andTami R. Argo, PharmD, MS, BCPPDivision o f P harmac.y Practice, College o f Pharmac.y, Unive rsityo~Texa s at Austin, Au stin, TexasA B S T R A C T

B a c k g r o u n d : Pa l ipe r idone , whic h i s a va i l a b l e i ne x t e nde d- r e l e a se (E R) t a b le t s , wa s a pp r ove d by t he USF o o d a n d D r u g A d m i n i s t r a t io n i n 2 0 0 7 f o r th e a c u t ea nd m a in t e na nc e t r e a tm e n t o f s c h i z ophr e n i a. I t i s t hese ve n th se c ond- ge ne r a t i on a n t i psyc ho t i c ( SGA) to bein t r oduc e d t o t he US m a r ke t . Pa l i pe r idone i s t he majora c t i ve m e ta bo l i t e o f r i spe r idone , a n e s t a b l i she d a n t i -psyc ho t i c a ge n t .

Objec t ive : This a r t ic le reviews the ava i lable l i te ra -t u r e o n t h e p h a r m a c o d y n a m i c s , p h a r m a c o k i n e t ic s ,c l inica l e ff icacy, and tole rabi l i ty of pa l ipe r idone .

M e t h o d s : A c o m p r e h e n s i v e s e a r c h o f M E D L I N Eus ing t he t e r m s paliperidone, 9-bydroxy-risperidone,a n d h we g a w a s p e r f o r m e d f o r th e y e a r s 1 9 5 0 t h r o u g hDec emb er 2007. Ar t ic les t ha t discussed the e f f icacy andto l e r a b i li t y o f 9 - hyd r oxy- r i spe r ido ne f o r m e d a s a m e -t a bo l i t e o f r i spe r idone we r e e xc lude d ; a l l o the r s we r einc luded. Abst rac ts and poste r s presented a t r ecent na-t i ona l a nd i n t e r na t i ona l s c i en t if i c m e e t ings we r e a l soinc lude d i n t he r e vi e w .

Results: At the rapeut ic doses (3-12mg) , pa l iper idoneER fol lows l inear pharmacok ine t ics . L ike tha t of i ts par -e n t d r ug , pa l i pe ridone 's m e c ha n i sm of a c t i on i s t hough tto be t h r o ug h a n t a gon i s t i c a c t ions a t d opa m ine D 2a nd se r o ton in - 2A r e c e p to r s . I n v ivo s tud i e s sugge s tt ha t t he c y toc hr o m e P450 e nz ym e sys te m p la ys a m in i -m a l r o l e i n pa l i pe r idone m e ta bo l i sm , w i th none o fthe m e ta bo l i t e s a c c oun t ing f o r > 10% of a dose. T hem a jor i t y ( 59%) o f pa l i pe r idone i s e l im ina t e d t h r oughthe k idne ys a s unc ha nge d d r ug . T he r e su l t s o f t h r e e6- we e k , r a ndom iz e d , doub le - b l i nd , pa r a l l e l- g r oup t r i -a ls i nd i c a t e d t he e f f ic a c y o f pa l i pe r idone E R c om pa r e dwi th p l a c e bo in t he t r e a tm e nt o f a c u t e e xa c e r ba t i onsof sc h i z ophr e n i a , w i th r e sponse r a t e s r a ng ing f r om3 9 . 8 % t o 6 1 . 0 % f o r p a l i p er i d o n e E R , c o m p a r e d w i t h18 .3% to 34 .0% f or p l a c e bo . Dur ing a 52- we e k ,

doub le-bl ind, re lapse-prevent ion t r ia l , the t ime to 2 5%of pa t ients exp er ienc ing a recur rence was 83 days forpa l i pe r idone E R, c om p a r e d w i th 23 da ys f o r p l a c e bo .T he p r o por t i ons o f pa ti e n t s i n t he 6 - we e k t ri a ls wh or e p o r t e d a t l e a s t 1 e x t r a p y r a m i d a l s y m p t o m - r e l a t e da d v e rs e e v e n t w e r e 1 3 % , 1 0 % , 2 5 % , 2 6 % , a n d 2 4 %for pa l iper idone ER 3, 6 , 9 , 12, and 15 mg/d, r espec-t ive ly; the pooled inc idence ra te was not s ta t i s t ica l lyd i f fe r e n t f r om tha t w i th p l a c e bo ( 11%) . He a da c h e a ndinsomnia were the most common adverse events in pa-t ients treated with paliper idone ER in the 6-week tr ials(pooled da ta : 11% -18 % and 4 % -14 % , respect ive ly) . Inthe relapse-prevention tr ial , the incidence of prolactin-r e l a t e d a dve r se e ve n t s wa s 4% f or pa l i pe r idone E Ra nd 0% f or p l a c e bo .

C o n c l u s i o n s : Cur r e n t e v ide nc e suppor t s t he e f fi c a-c y a nd t o l e r a b i l i t y o f pa l i pe r idone E R in t he a c u t e a ndl o n g - t e r m t r e a t m e n t o f s c h i z o p h r e n i a . R a n d o m i z e d ,he a d - to - he a d c om p a r i sons w i th o th e r SGAs, pa r ti c u -l a r ly r i spe r idone , a r e ne e d e d t o de f ine the r o l e o f pa l i-pe r idone E R in t he t r e a tm e nt o f s c h i z ophr e n i a . (ClinThe~, 2 0 0 8 ; 3 0 : 2 3 1 - 2 4 8 ) 2 0 0 8 E x c e r p ta M e d i c aInc.

K e y w o r d s : p a l i p e r i d o n e , 9 - h y d r o x y - r i s p e r i d o n e ,I nve ga , s c h i z ophr e n i a , pha r m a c o logy , t o l e r a b i l i t y ,eff icacy.

I N T R O D U C T I O NSchizophrenia i s a disabl ing and devasta t ing i l lness .T he Diagnostic and Statistical Manual of Mental Dis-orders, 4th Edition (DSM -IV) ] de f ines sc h i z op hr e n i aA c c e p t e d o r p u b l i c a ti o n J a n u a r y 9 , 2 0 0 8 .d o i : l 0 . 1 0 1 6 / j . c l in t h e r a . 2 0 0 8 . 0 2 . 0 1 10 1 4 9 - 2 9 1 8 / $ 3 2 . 0 0 2 0 0 8 E x c e r p t a M e d i c a I nc . A ll r i g h t s r e s e r ve d .

February 20 08 231


2/18

Clin ica l Th erap eu t ic s

ba se d on t he p r e se nc e o f pos i t i ve a nd ne ga t ive sym p-tom s a nd de t e r io r a t i on i n i n t e r pe r sona l a nd oc c upa -t i ona l r e l a t ionsh ips ove r 6 m onth s o r m or e . F i rs t -gen eration (con vention al , typical) an tipsycho tics (FGAs)have been ava i lable as t r ea tm ent opt ions for >60 years .How e ve r , t he se a ge n t s ha ve be e n a s soc i a t e d w i th ar i sk of ext rapyram ida l symptom s (EPS) and ta rdive dys-k ine s i a ( T D) due t o dopa m ine D~- r e c e p to r b loc ka dein t he n ig r os t r i a t a l pa thw a y . ~ P r ob l e m s o f t o l e r a b i l i t ywi th t he FG As l e d to a ne e d f o r m o r e e f f ic a c ious a ndbe t t e r t o l e r a t e d t r e a tm e nt op t ions f o r t he m a na ge -m e nt o f s c h i z ophr e n i a a nd o the r psyc ho t i c il lnes se s.

T he pa s t de c a de ha s se e n the i n t r oduc t ion o f s e c ond-ge ne r a t i on a n t i psyc ho t i c s ( SGAs) , i nc lud ing c loz a p ine ,o l a nz a p ine , r i spe r idone , que t i a p ine , z ip r a s idone , a r i -p ip r a z o l e , a nd pa l i pe r idone . T he SGAs a r e i nd i c a t e df or t he t r e a tm e n t o f s c h i z ophr e n i a a nd sc h i z oa f fe c t ivedisorder . 3 In a ddi t io n, a l l SGAs ex cept c loz apine a rea p p r o v e d f o r t h e t r e a t m e n t o f b i p o l a r m a n i a , a n dque t i a p ine ha s a n a dd i t i ona l i nd i c a t i on f o r t he t r e a t -me nt of bipo lar depress ion. 4,5 Severa l s tudies h avec om pa r e d t he e f f ic a c y a nd t o l e r a b i li t y o f FGAs a ndSGAs6 ,7 ; howe ve r , no c l e a r c onc lus ions we r e r e a c he dr e ga r d ing t he i r r e la t i ve a dva n ta ge s a nd d i sa dva n ta ge s .I n t he t r e a tm e nt o f s c h i z ophr e n i a a nd sc h i z oa f f e c t i ved i sor de r , SGAs m a y pr ov ide be t t e r ne ga t ive sym ptomc ont r o l , l es s dyspho r i a , le ss im p a i r m e n t o f c ogn i t i on ,and a low er r i sk o f TD tha n FGAs. 8,9 Ho wev er , c lini -c a l tr i al s a n d pos tm a r ke t i ng su r ve i ll a nc e o f t he SGAsha ve f ound subs t a n t i a l we igh t i nc r e a se s a s soc i a t e dwi th se ve r a l o f t he se a ge n t s , pa r t i c u l a r ly c loz a p inea nd o l a nz ap ine .1 We igh t ga in m a y ha ve a subs t a n t i a limp act on pa t ients ' se l f -percept ion, as wel l as on long-te rm com pl iance . 11 Add i t iona l ly , weight ga in assoc ia tedwi th t he SGAs m a y ha ve s ign i f i c a n t m e dic a l c onse -que nc e s : c om p l i c a t i ons t ha t ha ve b e e n a s soc i a t e d w i thobe s i t y in ge ne r a l popu la t i on sa m ple s i nc lude os t e oa r-t h r it i s , hype r t e ns io n , c o r o na r y a r t e r y d i se a se , dys li p i-demias , type 2 diabe tes mel l i tus , r espi ra tory di f f icul -t ies, stro ke, sleep ap nea , an d c er ta in typ es of cancer . 1~,13T ype 2 d i a be t e s ha s be e n f ound to be m or e p r e va l e n ti n pa t i e n t s w i th sc h i z ophr e n i a ( 10 .8%) tha n i n t hegene ra l pop ula t io n (8.7% ) . 14,15 Oth er m etabo l ic r i skshave been found in pa t ients wi th a f i r s t episode ofschizoph renia before the ini t ia t ion of d rug therapy.16-~T he po t e n t i a l a dd i t i ona l m e ta bo l i c bur de n o f SGAthe r a p y in pa t i en t s w i th sc h i z oph r e n i a is a c onc e r n .

C l in i c i a ns f a c e d w i th c hoos ing f r om a num be r o fa va i l a b l e a n t i psyc ho t i c t r e a tm e nt s m us t t a ke m a ny

f a c to r s i n to c ons ide r a t i on , i nc lud ing pa t i e n t p r e f e r -ence , cos t , ava i labi l i ty , dosing schedu le , and tole rabi l i -ty . Pa l iper idone ,* which i s ava i lable in extended-r e l e a se ( E R) t a b l e t s , wa s a ppr ove d by t he US Fooda nd D r ug Adm in i s t r a t i on ( FDA) in 2007 f o r t he a c u t ea nd m a in t e na nc e t r e a tm e nt o f s c h i z ophr e n i a ( F igure ).I t is t he se ve n th SGA to be i n t r o duc e d t o t he US m a r -ke t . This a r t ic le reviews the ava i lable l i te ra ture on thepha r m a c od yna m ic s , pha r m a c okine t i c s , cl i n ic a l e ff i ca -c y , a nd t o l e r a b i l it y o f pa l i pe r idone E R in t he m a na ge -m e nt o f s c h i z ophr e n i a a nd o the r r e l a t e d psyc ho t i cdisorders .M E T H O D SA c o m p r e h e n s i v e s ea r c h o f M E D L I N E u s in g t h e t e r m spaliperidone, 9 -hydroxy-risperidone, a n d Inve~a w aspe r f o r m e d f o r the ye a r s 1950 th r o ugh D e c e m b e r 2007 .Ar t ic les tha t discussed the e f f icacy and tole rabi l i ty of9 - hyd r oxy- r i spe r ido ne f o r m e d a s a m e ta bo l i t e o f ri s-pe r idone we r e e xc lude d ; a l l o the r a r t i c l e s we r e i n -c lude d . Abs t r a c t s a nd pos t e r s p r e se n t e d a t r e c e n t na -t i ona l a n d i n t e r na t i ona l s c ie n t if i c m e e t ings we r e a l soinc lude d i n t he r e v i ew .P H A R M A C O D Y N A M I C SPa l ipe r idone , o r 9 - hydr ox y- r i spe r idone , i s t he m a jora c ti ve m e ta bo l i t e o f r i spe r idone . I t b inds t o bo th D 2a nd se r o ton in - 2A ( 5- HT2A) r e c e p to r s , a nd a n t a go n i sma t t he se re c e p to r s i s t hou gh t t o a c c ou n t f o r i ts t he r a -peut ic ac t ivi ty in schizop hrenia . 2-23

Al l SGAs e xh ib i t e i t he r D 2 a n t a gon i sm or pa r t i a la gon i sm , whic h c on t r i bu t e s t o bo th a n t i psyc ho t i c e f -f i ca c y a nd unde s i r a b l e E PS .24,25 I t has bee n hy po the -s iz e d t ha t a n t i psyc ho t i c a ge n ts w i th r a p id d i s soc i a t ionf r om the D 2 r e c e p to r ( eg , cloz a p ine ) m a y be a s soc i a t e dwi th a l ow e r i nc ide nce o f E PS tha n a ge n ts suc h a s ha lo -pe r ido l a nd r i spe r idone , whic h ha ve sus t a ine d h igh D 2oc c upa nc y .26 In one s tudy us ing in vi t ro models wi ththe h um a n c lone d D 2 L ong r e c e p to r i n t i s sue c u l t u r ece ll s, the t ime to 50% dissoc ia t ion f rom the D 2 recep-to r wa s f ound to be 60 se c onds f o r pa l i pe r idone2 n m o l / L , c o m p a r e d w i t h 2 7 m i n u t es f o r r i s p e ri d o n e2 n mol /L . 27 Theore t ica l ly , mo re rapid dissoc ia t ion f ro mthe D 2 r e c e p to r c o u ld t r a ns l a t e i n to a l ow e r i nc ide nc eof E PS wi th pa l i pe r idone c om pa r e d w i th r i spe r idone .Howe ve r , da t a f r om c l i n i c a l t r i a l s i nd i c a t e t ha t l i ker i spe r idone , pa l i pe r idone i s a s soc i a t e d w i th a dose -* T r a d e m a r k : I n v e g a M ( J a n s s e n L . P . , T i t u s v i l l e , N e w J e r se y ).

2 3 2 V o l u m e 3 0 N u m b e r 2


3/18

J . A . F o w l e r e t a l .

P a l i p e r i d o n eN - - O

H /

Risperidone N OO

F i gu r e . S t r u c t u r e s o f p a l i p e r i d o n e a n d r i s p e r i d o n e .

related increase in EPS within the effective dosingrange .=8-31 An other s tudy us ing postm or tem norm alhu ma n bra in t i ssue fou nd tha t the equi l ibr ium dissoc ia -t ion c onstant (Kd) a t the D= receptor was s imi la r forpa l iper idone (mean [SE] , 2 .8 [0 .3] ) and r i speridone(m ean [SE], 3.7 7 [0.04]). =1 Differences in antip sych oticaff inity (Kd) for the D= recepto r appea r to be dr ive n bydifferences in rates of dissociation (kerr) rat he r tha n ra tesof association (ken).=6 The refore, the f inding th at paliper i-done and r i speridone have a s imi la r Kd, wh ere Kd = k e jken, suggests that paliper idon e does n ot dissociate mo rerapidly fro m the D= receptor than r isperidone.

S im i l ar ly t o r i spe r idone , pa l i pe r idone b inds s t r ong-ly to th e 5-HT=A recep tor (K = 0.43) , wi th no s ignif i-can t a f f ini ty for o ther se roto nin recep tor sub types . =,=1An ta gon i sm a t t he 5 - HT = A r e c e p to r i n t he n ig r os t ri -a t a l d o p a m i n e p a t h w a y c a u s e s d o p a m i n e r e l e a s e b yb loc k ing t he i nh ib i t o r y e f f e c ts o f s e r o ton in . T he r e f o r e ,5 - HT = A a n t a gon i sm i s t hough t t o c on t r i bu t e t o t helower r i sk of EPS assoc ia ted wi th SGAs. A s imi la r e f -f e c t o f 5 -HT = A b loc ka d e i n t he m e soc or t i c a l dopa m inep a t h w a y i s t h o u g h t t o c o n t r i b u t e to i m p r o v e m e n t i nne ga t ive sy m pto m s o f sc h i z ophr e n i a . =4

In addi t ion to i t s antagonis t ic e f fec ts a t the D= and5-HT=A receptors , pa l iper idone has ac t ivi ty a t severa l

other receptor types . I t ac ts as an antagonis t a t o1-and o=-adrenergic recepto rs , but has no a f f ini ty for131- an d ]3=-adrenergic rec ep to rs Y o-Adrenergic bloc k-a de a c c oun t s f o r t he i nc r e a se d r i sk o f o r thos t a t i chypo te ns ion a s soc i a te d w i th pa l i pe r idone . = 324 Anta go-n i sm a t h i s t a m ine -1 r e c e p to r s m a y c on t r i bu t e t o se da -t ive adverse e f fec ts and weig ht ga in in pa t ients t r ea tedwi th pa l iper ido ne . =3,> Pa l iper ido ne ha s no a f f ini ty forc ho l iner g i c m usc a r in i c re c e p to r s a nd w ould no t be e x-pec ted to c ause ant ich ol inerg ic adverse e f fec ts such asdr y m ou th a nd c ons t i pa t i on . =3

Pa l ipe r idone E R t a b l e t s c on t a in a r a c e m ic m ix tu r eof (+) - and ( - ) -pa l iper idone . In vi t ro da ta indica te tha tt he de x t r o a nd l e vo e na n t iom e r s o f pa l i pe r idone ha ves im i l a r pha r m a c o log i c a c t i v i t yYP H A R M A C O K I N E T I C SA single-dose s tudy in hea l thy subjec ts (2 males , 2 fe -m a le s ) de t e r m ine d t ha t t he T m ax f o r pa l i pe r idone E R6 m g w a s - 24 hour s ( r a nge , 23 .1 - 29 .0 hour s ) . ==Simi la r f indings w ere repor ted in a s tudy in 75 h ea l thysub je c ts who r e c e ive d pa l i pe r idone E R 12 m g/d f o r5 o r 6 days . 3= The t l /= of pa l ip er idon e i s -23 hou rs ;therefore , s teady-s ta te conc ent ra t ions a re a t ta ined w i th-in 4 to 5 day s o f the star t of d ose escalat io n. ==,33,34

F e b r u ar y 2 0 0 8 2 3 3


4/18

Clin ica l Th erap eu t ic s

Pa l ipe r idone f o l l ows l i ne a r k ine t ic s w i th in t h e r e c om -m e nde d c l i n i c a l dose r a nge ( 3 - 12 r a g /d ) . E e r e de ke nse t a l 3~ r e por t e d a pe a k - to - t r oug h va r i a t i on o f 38 % f o rpa l i pe r idone 12 m g, a f l uc tua t i on i nde x m uc h lowe rtha n ha s b e e n r e por t e d f o r im m e dia t e - r e l e a se ( IR)pa l i pe r idone o r r i spe r idone Y T he a bso lu t e b ioa va i l -a b i l i t y o f pa l i pe r idone E R i s 28%, c om pa r e d w i th106 % for the IR form ula t io n. ~3,3s This low er b io-ava i labi l i ty i s l ike ly the e f fec t of pa l iper idone ER'so s m o t i c c o n t r o l l e d - r e l e a s e o r a l d e l i v e r y s y s t e m( OROS) , whic h r e l e a se s pa l i pe r idone p r im a r i l y i n tothe c o lon , whe r e a bsor p t i on i s l owe r . A l though thepa c ka ge i nse r t s t a t e s t ha t pa l i pe r idone E R c a n beg ive n w i thou t r e ga r d t o m e a l s , i nc r e a se s i n Cm ax a ndA U C ( 6 0 % a n d 5 4 % , r es p e ct iv e ly ) w e r e f o u n d i nhe a l t hy sub j e c t s wh o r e c e ive d pa l i pe r idone E R in c on-junc t i on w i th a h igh- f a t /h igh- c a lo r ie m e a l . ~3

T he a ppa r e n t Vd of pa l i pe r idone E R i s 487 L . Pal i-pe r idone E R ha s 74% p l a sm a pr o t e in b ind ing , p r i -mar i ly to the (*-ac id glycoprote in (c~I -AGP) . In ac om pa r a t i ve s t udy i n 10 sub j e c t s w i th m ode r a t e he -pa t i c im pa i r m e nt ( C hi ld - Pugh c la ss B , to t a l s c or e 7 - 9 )a nd 10 he a l t hy sub j e ct s , 33 l owe r p l a sm a pr o t e in b ind-ing wa s r e por t e d i n t he g r oup w i th he pa t i c im pa i r -m e nt . T h i s d i f f e r e nc e wa s l i kely a t tr i bu t a b l e t o l ow e rleve ls o f c~I-AGP in those w i th hep a t ic imp ai rm ent . Ase xpe c t e d , t he l ow e r p l a sm a p r o t e in b ind ing r e su l t e d ina h ighe r unbound f r a c t i on o f pa l i pe r idone i n sub j e c t sw i t h h e p a t i c i m p a i r m e n t c o m p a r e d w i t h h e a l t h y s u b -jects (35% vs 28% , r e spec t ive ly ). A l thou gh the a u-t h o r s d i d n o t s p e c u l a t e o n w h y l o w e r t o t a l p l a s m apa l ipe r idone c o nc e n t r a t i ons w e r e se e n i n sub j e c ts w i thm o d e r a t e h e p a ti c i m p a i r m e n t c o m p a r e d w i t h h e a l t h ysub je c t s , i t i s poss ib l e t ha t t he l owe r c onc e n t r a t i onswe r e due t o t he a va i l a b i l i t y o f unbound d r ug t o bem e ta bo l i z e d a nd /o r e l im ina t e d . How e ve r , i t wa s de t e r -m ine d t ha t a f t e r a d jus tm e n t f o r l owe r le vel s o f p l a sm apr o t e in b ind ing , p l a sm a a nd u r ine e xposur e t o un-bound f r a c t i on wa s s im i l a r be twe e n the 2 g r oups .T he f i nd ings o f i n v i t ro s t ud ie s sugge s t e d i nvo lve -m e n t o f t h e c y t o c h r o m e P 4 50 (C Y P ) 2 D 6 a n d 3 A 4i soz ym e s i n p a l i pe r idone m e ta bo li sm S3; howe ve r , thef indings of in vivo s tudies suggested tha t these en-z ym e s p l a y a sm a l l r o le i n t he m e ta bo l i sm of pa l i pe ri -d o n e E R , w i t h n o n e o f t h e m e t a b o li t es a c c o u n t i n g f o r> 10% of a dose . ~3 I n a s t udy i n w hic h 5 he a l t hy m a lesubjec ts (3 CY P2D6 extensive metabol izers and 2 poo rm e ta bo l i z e r s o f de x t r om e thor pha n) r e c e ive d a s i ng l edose o f 14C-pa liper idone IR 1 mg, e l imin a t ion was

pr im a r i l y v i a t he k idne ys ( 59 .0% a s unc ha ng e d d r ug)th r ou gh a c t ive se c r e ti on in t he r e na l t ubu l e by wa y o fa n o r ga n i c c a t i on sys t em . 34 Only a sm a l l por t i on o fdr ug wa s e l im ina t e d t h r ough the l i ve r ( 11 .4%) . Ad-d i t iona l ly , on ly a sm a l l p r op or t i on o f m e ta bo l i t e s wa sf oun d in t he u rine , a c c oun t ing f o r < 6 .5% of t he dose ,a nd on ly 0 .4% to 0 .9% wa s f ou nd in t he fe ce s. Noove r a l l pha r m a c ok ine t i c d i f f e re nc e s we r e obse r ve dbe twe e n e x t e ns ive a nd poo r m e ta bo l i z er s . T he r e su l t sof this s tud y sug gested a low r i sk for c l inica l ly signi fi -c a n t CYP in t e r a c ti ons w i th pa l i pe r idone .D R U G I N T E R A C T I O N ST he e f f e c t s on pa l i pe r idone E R pha r m a c okine t i c s o fc o a d m i n i s t r a t i o n w i t h a p o t e n t C Y P 2 D 6 i n h i b i t o r( pa r oxe t ine ) a nd a po t e n t o r ga n i c c a t i on i nh ib i t o r( t r im e thop r im ) ha ve be e n e x a m ine d . B e r wa e r t s e t a136s tud i e d t he pha r m a c okine t i c e f f e c t s o f pa r oxe t ine ona s ing l e dose o f pa l i pe r idone E R in a r a ndom iz e d ,ope n- l a be l , doub le - c r ossov e r s t udy i n 50 he a l t hy m a lesub j e c t s . Sub je c t s we r e r a ndom iz e d t o r e c e ive e i t he rp a l ip e r i d o n e E R 3 m g o n d a y 1 o r p a r o x e t i n e 2 0 m gon da y s 1 t o 13 , w i th pa l i pe r idone E R 3 m g g ive n a sa s ing l e dose on d a y 10 . Af t e r a 14- t o 28 - da y wa sho u tpe r iod , sub j e c t s we r e c r osse d ove r t o t he a l t e r na t i ver e g im e n . M e a n ( SD) Cmax wa s num e r i c a l l y l owe r f o rpa l i pe r idone E R a lone ( 5 .10 [ 1 .92] ng /m L ) t ha n f o rpa l i pe r idone E R p lus pa r oxe t ine ( 5 .72 [ 2.21] ng /m L ) ;howe ve r , w i th a 90% CI o f 0 .98 t o 1.22, t h e t r e a t m e n tr a t i o r e m a ine d w i th in t he a c c e p t e d b ioe qu iva l e nc ei n t e r v a l ( 8 0 % - 1 2 5 % ) . Al though the f i nd ings d id no tsuggest a c l inica l ly s igni f icant inte rac t ion be tweenpa l ipe r idone E R a nd pa r oxe t ine 20 r a g , t he po t e n t i a lf o r i n t e r a c t i ons w i th h ighe r dose s o f pa r oxe t ine ,w h i c h w o u l d y i e l d m o r e p o t e n t C Y P 2 D 6 i n h i b i t i o n ,has y e t to be s tudied. Ad di t iona l ly , the e f fec t on p a l i -p e r i d o n e E R p h a r m a c o k i n e t i c s o f d r u g s t h a t i n h i b i tbo th CYP2D6 a nd CYP3A4 ( e g , f l uoxe t ine ) ha s ye tt o be e xa m ine d . Whi l e t he i n t e r a c t i on , i f i t e x i s t e d ,would be un l ike ly t o c a use t ox i c i t y be c a use o f pa l i -pe r idone ' s w ide t he r a pe u t i c i nde x , pa t i e n t s r e c e iv ingc o n c o m i t a n t p a l i p er i d o n e E R a n d C Y P 2 D 6 / 3 A 4 i n-h ib i t o r s m igh t be m or e l i ke ly t o e xpe r i e nc e a dve r see f fe c t s suc h a s E PS or hype r pr o l a c t i ne m ia .

T h e e ff ec ts o f t r i m e t h o p r i m o n t h e p h a r m a c o k i n e t -i cs o f pa l i pe r idone E R w e r e e xa m in e d in a r a ndo m -iz e d , ope n- l a be l , c r os sove r s t udy i n 30 he a l t hy m a lesubjec ts . 37 Subjec ts w ere a l loca ted to rece ive e i therp a l i p e r i d o n e E R 6 m g o n d a y 1 o r t r i m e t h o p r i m

2 3 4 V o l um e 3 0 N u m b e r 2


5/18

J . A . F o w l e r e t a l .

2 0 0 m g BI D f r o m d a y s 1 t o 8 , w i t h p a l i p e r i d o n e E R6 mg a d d e d o n d a y 5 . A f t e r a 1 4 - d a y w a s h o u t p e r i o d ,sub jec t s c rossed over to the a l t e rna t ive reg imen . Val -ues fo r C . . . . l as t quan t i f i ab le AU C, and rena l c l ear-a n c e o f p a l i p e r i d o n e E R f el l w i t h i n t h e a c c e p t e d r a n g ef o r b i o e q u i v a l e n c e . T h e r e w a s a n a p p a r e n t i n -c r e a s e i n t h e u n b o u n d f r a c t i o n w h e n p a l i p e r i d o n eE R w a s c o a d m i n i s t e r e d w i t h t r i m e t h o p r i m c o m p a r e dw i t h a d m i n i s tr a t i o n w i t h o u t t r i me t h o p r i m ( 2 9 . 7 % v s2 5 . 7 % , r e s p e c t i v e l y ) a n d a d e c r e a s e i n t o t a l e x p o s u r e(356 vs 391 ng /mL ) an d t l /~ (21 .8 vs 26 .8 hours ) ( s t a-t i s t i ca l s ign i f i cance no t repor t ed ) . Thus , d rug-d rugi n t e r a c t i o n s a p p e a r t o b e u n l i k e l y w h e n p a l i p e r i d o n eE R i s c o a d mi n i s t e r e d w i t h o t h e r d r u g s e x c r e t e d p r i -ma r i l y t h r o u g h t h e r e n a l t u b u l e .

N o p u b l i s h e d s t u d i e s w e r e id e n t i fi e d t h a t e v a l u a t e dthe e f fec t s on Cmax o r A U C w i t h c o n c o m i t a n t u s e o fp a l i p e r i d o n e E R a n d e t h a n o l .C L I N I C A L E F F I C A C YRa n d o mi z e d c o n t r o l l e d t r i a l s h a v e e v a l u a t e d p a l i p e r i -d o n e E R i n t h e a c u t e a n d ma i n t e n a n c e t r e a t me n t o fs c h i z o p h re n i a . A v a i la b l e p r o s p e c t iv e , r a n d o m i z e d c o n -t ro l l ed t r i a l s o f pa l iper idone ER in pa t i en t s wi thschiz oph renia are sum m ariz ed in T able I . 28-3,38,39

I n s t r u me n t s u s e d t o me a s u r e t r e a t m e n t e f f ic a c y i nthese s tud ies inc luded the Pos i t ive and Negat ive Syn-drome Sca le (PANSS) , t he Cl in i ca l Globa l Impress ionSever i ty o f I ll ness sca le (CG I-S) , and the Person a l a ndSocia l Per fo rm ance sca le (PSP) . The PANSS i s a 30- i t ems c a le d e s i g n e d t o m e a s u r e t h e s e v e r i ty o f p s y c h o p a -t h o l o g y i n p a t i e n t s w i t h s c h i z o p h r e n i a o r o t h e r p s y -cho t i c d i so rders . I t measures pos i t ive and nega t ivesymptoms , as wel l as genera l psychopatho logy . EachPA N SS i t e m i s s c o r e d o n a 7 - p o i n t a n c h o r e d L i k e r tsca le , w i th h igher sco res ind ica t ing g rea te r sever i ty o fs y mp t o ms . 4 A 3 0 % r e d u c t i o n i n PA N SS t o t a l s c o r e isgenera l ly cons idered ind ica t ive o f a c l in i ca l ly s ign i f i -c a n t i m p r o v e m e n t i n s y m p t o m s a n d h a s b e e n f o u n d t oc o r r e s p o n d t o a CG I I mp r o v e me n t ( CG I - I ) s c a l e r a t -ing o f m in im a l l y im pro v e d . 41 A 5 0 % r e d u c t i o n i nPA N SS t o t a l s c o r e r e p r e s e n t s a mo r e r o b u s t r e s p o n s e ,c o r r e s p o n d i n g t o a CG I - I r a t i n g o f m u c h i m p r o v e d .Based on a fac to r ana lys i s o f PANSS scores in s tud ieso f r i sper idone , M ard er e t a142 descr ibe d the PAN SS int e r ms o f 5 d i me n s i o n s . T h e PA N SS Ma r d e r f a c t o r s ,w h i c h w e r e u s e d a s s e c o n d a r y e f f i c a c y me a s u r e s i n t h es t u d i e s o f p a l i p e r i d o n e E R , i n c l u d e p o s i t i v e s y mp -t o ms , n e g a t i v e s y mp t o ms , d i s o r g a n i z e d t h o u g h t , u n -

con t ro l l ed hos t i l i t y /exc i t ement , and anx ie ty /depress ion .W h i l e t h e PA N SS me a s u r e s s p e c i f i c p s y c h o p a t h o l o g i csymptoms , the CGI-S rep resen t s the c l in i c i an ' s g loba las sessm ent o f the sever i ty o f a pa t i en t ' s i ll ness on as t andar d ized sca le. 43 Scores on the CGI-S range f rom1 (not a t a l l i l l ) to 7 ( am ong the m os t e x t r e m e ly i l l ) .The PSP i s a s ing le- i t em, 100-po in t , c l in i c i an - ra t edsca le des igned to measure pa t i en t s ' persona l and soc ia lfunct ioning in 4 main areas: social ly useful act ivi t ies( i n c l u d i n g w o r k a n d s t u d y ) , p e r s o n a l a n d s o c i a lrelat ionships , sel f-care, and dis turbing and aggress ivebeha viors . 44 The scale is d ivided into 10-p oint in terva ls ,wi th a sco re o f 1 to 10 rep resen t ing l ack o f au tonomyin bas ic func t ion ing and a sco re o f 91 to 100 rep resen t -ing excel lent funct ion in al l 4 main areas .A c u t e T r e a t m e n t

Three s imi l a r ly des igned randomized con t ro l l ed t r i -a ls have ev a lua ted the sh or t - t e rm ef f i cacy o f pa l iper i -d o n e E R f o r th e t r e a t me n t o f a d u l t p a ti e n t s w i t hsch izophren ia us ing in t en t - to - t rea t ana lys i s (pa t i en t sw h o r e c e i v e d a t l e a s t 1 d o s e o f s t u d y me d i c a t i o n a n dhad a t l eas t 1 pos tbas e l ine e f f i cacy as sessment ) . 28-3O l a n z a p i n e w a s i n c l u d e d a s a n a c t i v e c o n t r o l i n t h e s es t u d i e s a n d w a s n o t i n c l u d e d i n t h e a n a l y s e s o f t r e a t -ment eff icacy.

Kane e t a128 cond ucted an in t e rna t iona l , mul t i cen ter ,6 - w e e k , r a n d o m i z e d , d o u b l e - b l i n d t ri a l c o m p a r i n gp a l i p e r i d o n e E R w i t h p l a c e b o i n p a t i e n t s w i t h a nacu te exacerba t ion o f sch izophren ia . E l ig ib le pa t i en t sw e r e r e q u i r e d t o h a v e a D S M - I V d iagnos i s o f sch izo-phren ia fo r a t l eas t 1 year befo re sc reen ing and ab a s e l i n e PA N SS t o t a l s c o r e b e t w e e n 7 0 a n d 1 2 0 . T h ep r i ma r y e f f ic a c y me a s u r e w a s t h e c h a n g e i n PA N SSto ta l s co re f rom base l ine to end po in t . Secondary e f -f i ca c y me a s u r e s i n c l u d e d t h e c h a n g e s f r o m b a s e l in et o e n d p o i n t i n s c o r e s o n t h e PA N SS Ma r d e r f a c t o r s ,CG I - S , a n d PSP . T h e o n s e t o f t h e r a p e u t i c e f f e c t w a sa s s e s s e d b a s e d o n t h e f i r s t s c h e d u l e d o b s e r v a t i o np o i n t a t w h i c h t h e c h a n g e f r o m b a s e l i n e i n PA N SSto ta l s co re was s ign i f i can t ly d i f fe ren t in the pa l iper i -d o n e E R g r o u p c o m p a r e d w i t h t h e p la c e b o g r o u p .

E l ig ib le pa t ien t s w ere rand om ized to rece ive pa l i -p e r i d o n e E R 6 mg / d ( n = 1 2 3 ) , p a l i p e r i d o n e E R9 mg/d (n = 122) , p a l i p e r i d o n e E R 1 2 mg / d ( n = 1 3 0 ) ,o l anza p ine 10 mg/d (n = 128) , o r p l aceb o (n = 127) . ~8Sy mp t o ms w e r e me a s u r e d ( PA N SS a n d CG I - S ) a tbase l ine ; on da ys 4 , 8, and 15 ; and we ek ly thereaf t e r .Pa t i en t s were hosp i t a l i zed fo r a t l eas t t he f i r s t 14 days

F e b r u ar y 2 0 0 8 2 3 5


6/18

o

2008 - paliperidone extended-release tablets for the acute and maintenance treatment of...

Documents