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Population pharmacokinetic modelling of aripiprazole and its active metabolite, dehydroaripiprazole, in psychiatric patients

Cited 33 time in Web of Science Cited 34 time in Scopus
Authors
Kim, Jung-Ryul; Seo, Hyo-Bum; Cho, Joo-Youn; Kang, Do-Hyung; Kim, Yong Ku; Bahk, Won-Myong; Yu, Kyung-Sang; Shin, Sang-Goo; Kwon, Jun Soo; Jang, In-Jin
Issue Date
2008-11-27
Publisher
Wiley-Blackwell
Citation
Br J Clin Pharmacol. 2008;66(6):802-10
Keywords
Antipsychotic Agents/administration & dosage/*pharmacokineticsCytochrome P-450 CYP2D6/genetics/pharmacokineticsDrug Interactions/geneticsDrug MonitoringGenotypeHumansMaleMental Disorders/*drug therapyMetabolic Clearance Rate/geneticsMiddle AgedModels, BiologicalPiperazines/administration & dosage/*pharmacokineticsPolymorphism, Genetic/geneticsQuinolones/administration & dosage/*pharmacokineticsYoung Adult
Abstract
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.
ISSN
1365-2125 (Electronic)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19032724

http://hdl.handle.net/10371/67544
DOI
https://doi.org/10.1111/j.1365-2125.2008.03223.x
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College of Medicine/School of Medicine (의과대학/대학원)Pharmacology (약리학전공)Journal Papers (저널논문_약리학전공)
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