Utjecaj farmakogenetičkih varijacija CYP2D6 i ABCB1 na liječenje pripravkom risperidona s produljenim oslobađanjem [Impact of pharmacogenetic variations of CYP2D6 and ABCB1 on the long-acting risperidone treatment]

Ganoci, Lana (2019) Utjecaj farmakogenetičkih varijacija CYP2D6 i ABCB1 na liječenje pripravkom risperidona s produljenim oslobađanjem [Impact of pharmacogenetic variations of CYP2D6 and ABCB1 on the long-acting risperidone treatment]. PhD thesis, Sveučilište u Zagrebu.

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Abstract

The practical relevance of polymorphisms of multidrug resistance protein (ABCB1) and breast cancer resistance protein (ABCG2) for treatment with long-acting intramuscular (LAI) risperidone is largely unknown. We explored the relationship between these polymorphisms and cytochrome P450 (CYP) 2D6 phenotype in their effects on drug disposition and clinical outcomes in adults with schizophrenia. In a 24-week observational study, patients initiated on LAI-risperidone (n=101) were genotyped enzymes (CYP2D6*3,*4,*5,*6,*41,dupl; CYP3A4*22,CYP3A5*3), transporters (ABCG2 421C>A; ABCB1 1236C>T, 2677G>T/A, 3435C>T) and evaluated for steady-state (weeks 6-8) plasma levels of dose-corrected risperidone, 9-OH-risperidone, risperidone+9-OH-risperidone (active moiety) and for symptom severity (Positive and Negative Syndrome Scale, PANSS, baseline, weeks 12 and 24). CYP2D6 normal/ultrarapid metabolizer (NM/UM) phenotype (vs. all others) was associated with 17-23% lower exposure in ABCG2 wild-type homozygotes, and with 43-55% lower exposure in ABCG2 variant allele carriers (reduced transporter function). ABCB1 polymorphisms had no effect. NM/UM phenotype tended to less PANSS reduction. ABCG2 variant allele was associated with 4-5-times higher odds of a relevant PANSS reduction, while ABCB1 predominantly wild-type genotype (normal transporter function) (vs. all others) was associated with 60-65% lower odds (effects unconditional on CYP2D6 phenotype). With ABCB1 predominantly wild-type genotype, active moiety level had no effect on clinical response; otherwise, the lower level was associated with a greater symptoms reduction. CYP2D6 phenotype effect on exposure to LAI-risperidone is relevantly conditional on ABCG2 421C>A polymorphism. ABCG2 and ABCB1 (1236C>T, 2677G>T/A, 3435C>T) polymorphisms effects on risperidone efficacy are clinically relevant and not related to systemic disposition.

Abstract in Croatian

Važnost polimorfizama proteina višestruke rezistencije, ABCB1 i ABCG2, za liječenje pripravkom risperidona s produljenim oslobađanjem (LAI-RIS) uglavnom nije poznata. Ispitali smo odnos između ovih polimorfizama i fenotipova citokroma P450 (CYP) 2D6 u njihovim učincima na bioraspoloživost lijeka i kliničke ishode u odraslih pacijenata sa shizofrenijom. U 24-tjednoj opservacijskoj studiji, pacijenti liječeni s LAI-RIS (n=101) bili su genotipizirani enzimi (CYP2D6*3,*4,*5, *6,*41, dupl; CYP3A4*22,CYP3A5*3), transporteri (ABCG2 421C>A; ABCB1 1236C>T, 2677G>T/A, 3435C>T). Ispitane su povezanosti ravnotežnih koncentracija risperidona (6. i 8. tjedan) ujednačenih prema dozi, risperidona, 9-OH-risperidona, risperidona + 9-OH-risperidon (ukupni aktivni lijek) s težinom simptoma bolesti (ocjenska ljestvica PANSS, početna vrijednost, 12. i 24. tjedan). Fenotip CYP2D6 normalni/vrlobrzi metabolizatori (NM/UM) (u usporedi s ostalima) povezan je sa 17-23% manjom izloženošću u homozigotnih nositelja divljeg tipa alela ABCG2 i sa 43-55% manjom izloženošću u nositelja varijantnog alela ABCG2 (smanjena funkcija transportera). Polimorfizmi ABCB1 nisu imali učinka. Za fenotip NM/UM uočena je tendencija manjeg smanjenja PANSS-a. Varijantni alel ABCG2 bio je povezan s 4-5 puta većim izgledima za relevantno smanjenje PANSS-a, dok je ABCB1 pretežno divlji tip genotipa (normalna funkcija transportera) (nasuprot svim ostalim) povezan s 60-65% nižim izgledima (učinci su neovisni o fenotipu CYP2D6). U osoba s ABCB1 pretežno „divljim“ genotipom, razina ukupne aktivnosti lijeka nije utjecala na klinički odgovor; u suprotnom, niža razina bila je povezana s većim smanjenjem simptoma. Učinak fenotipa CYP2D6 na izloženost LAI-RIS bitno je uvjetovan polimorfizmom ABCG2 421C> A. Učinci polimorfizma ABCG2 421C>A i ABCB1 (1236C> T, 2677G>T/A, 3435C>T) klinički su relevantni i nisu povezani sa sistemskom izloženosti lijeku.

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