Premium
Population pharmacokinetic modelling of aripiprazole and its active metabolite, dehydroaripiprazole, in psychiatric patients
Author(s) -
Kim JungRyul,
Seo HyoBum,
Cho JooYoun,
Kang DoHyung,
Kim Yong Ku,
Bahk WonMyong,
Yu KyungSang,
Shin SangGoo,
Kwon Jun Soo,
Jang InJin
Publication year - 2008
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2008.03223.x
Subject(s) - aripiprazole , cyp2d6 , nonmem , pharmacokinetics , population , pharmacology , pharmacogenetics , volume of distribution , medicine , population pharmacokinetics , active metabolite , metabolite , cytochrome p450 , chemistry , schizophrenia (object oriented programming) , psychiatry , genotype , metabolism , biochemistry , environmental health , gene
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Almost all reported studies have investigated the pharmacokinetics of aripiprazole in healthy volunteers. • The pharmacokinetics of dehydroaripiprazole have not been identified in a combined model with aripiprazole. WHAT THIS STUDY ADDS • The data on aripiprazole and dehydroaripiprazole in psychiatric patients were modelled jointly using a population approach. • The apparent clearance of aripiprazole in cytochrome P450 (CYP) 2D6 intermediate metabolizers (IM) was approximately 60% of that in CYP2D6 extensive metabolizers (EM) having two functional alleles, but the exposure to dehydroaripiprazole in CYP2D6 IM was similar to that in EM. AIMS The aims of this study were to develop a combined population pharmacokinetic model for both aripiprazole and its active metabolite, dehydroaripiprazole, in psychiatric patients and to identify to what extent the genetic polymorphisms of cytochrome P450 (CYP) enzymes contribute to the variability in pharmacokinetics (PK). METHODS A population pharmacokinetic analysis was performed using NONMEM software based on 141 plasma concentrations at steady state from 80 patients receiving multiple oral doses of aripiprazole (10–30 mg day −1 ). RESULTS A one‐compartment model with first‐order kinetics for aripiprazole and dehydroaripiprazole each was developed to describe simultaneously the concentration data. The absorption rate constant was fixed to 1.06 h −1 . The typical value of apparent distribution volume of aripiprazole was estimated to be 192 l. Covariate analysis showed that CYP2D6 genetic polymorphisms significantly influenced the apparent clearance of aripiprazole (CL/ F ), reducing the interindividual variability on CL/ F from 37.8% CV (coefficient of variation) to 30.5%. The CL/ F in the CYP2D6 IMs was approximately 60% of that in CYP2D6 EMs having two functional alleles. Based on the CYP2D6 genotype, the metabolic ratios were calculated at 0.20–0.34. However, the plasma concentration : dose ratios of dehydroaripiprazole were not different across the CYP2D6 genotype. CONCLUSIONS This population pharmacokinetic model provided an adequate fit to the data for both aripiprazole and dehydroaripiprazole in psychiatric patients. The usefulness of CYP genotyping as an aid to select the starting dose should be further investigated.