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

Jung Ryul Kim, Hyo Bum Seo, Joo Youn Cho, Do Hyung Kang, Yong Ku Kim, Won Myong Bahk, Kyung Sang Yu, Sang Goo Shin, Jun Soo Kwon, In Jin Jang

Research output: Contribution to journalArticle

32 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)802-810
Number of pages9
JournalBritish Journal of Clinical Pharmacology
Volume66
Issue number6
DOIs
Publication statusPublished - 2008 Dec 1

Fingerprint

Cytochrome P-450 CYP2D6
Psychiatry
Pharmacokinetics
Cytochrome P-450 Enzyme System
Population
Genetic Polymorphisms
Genotype
dehydroaripiprazole
Aripiprazole
Software
Alleles

Keywords

  • Aripiprazole
  • Cytochrome P450 2D6
  • Genetic polymorphism
  • Metabolite
  • Population pharmacokinetics

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology

Cite this

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

In: British Journal of Clinical Pharmacology, Vol. 66, No. 6, 01.12.2008, p. 802-810.

Research output: Contribution to journalArticle

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. / Population pharmacokinetic modelling of aripiprazole and its active metabolite, dehydroaripiprazole, in psychiatric patients. In: British Journal of Clinical Pharmacology. 2008 ; Vol. 66, No. 6. pp. 802-810.
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T1 - Population pharmacokinetic modelling of aripiprazole and its active metabolite, dehydroaripiprazole, in psychiatric patients

AU - Kim, Jung Ryul

AU - Seo, Hyo Bum

AU - Cho, Joo Youn

AU - Kang, Do Hyung

AU - Kim, Yong Ku

AU - Bahk, Won Myong

AU - Yu, Kyung Sang

AU - Shin, Sang Goo

AU - Kwon, Jun Soo

AU - Jang, In Jin

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N2 - 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.

AB - 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.

KW - Aripiprazole

KW - Cytochrome P450 2D6

KW - Genetic polymorphism

KW - Metabolite

KW - Population pharmacokinetics

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