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

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dc.contributor.authorKim, Jung-Ryul-
dc.contributor.authorSeo, Hyo-Bum-
dc.contributor.authorCho, Joo-Youn-
dc.contributor.authorKang, Do-Hyung-
dc.contributor.authorKim, Yong Ku-
dc.contributor.authorBahk, Won-Myong-
dc.contributor.authorYu, Kyung-Sang-
dc.contributor.authorShin, Sang-Goo-
dc.contributor.authorKwon, Jun Soo-
dc.contributor.authorJang, In-Jin-
dc.date.accessioned2010-06-07T05:45:46Z-
dc.date.available2010-06-07T05:45:46Z-
dc.date.issued2008-11-27-
dc.identifier.citationBr J Clin Pharmacol. 2008;66(6):802-10en
dc.identifier.issn1365-2125 (Electronic)-
dc.identifier.urihttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19032724-
dc.identifier.urihttps://hdl.handle.net/10371/67544-
dc.description.abstractAIMS: 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.en
dc.language.isoenen
dc.publisherWiley-Blackwellen
dc.subjectAntipsychotic Agents/administration & dosage/*pharmacokineticsen
dc.subjectCytochrome P-450 CYP2D6/genetics/pharmacokineticsen
dc.subjectDrug Interactions/geneticsen
dc.subjectDrug Monitoringen
dc.subjectGenotypeen
dc.subjectHumansen
dc.subjectMaleen
dc.subjectMental Disorders/*drug therapyen
dc.subjectMetabolic Clearance Rate/geneticsen
dc.subjectMiddle Ageden
dc.subjectModels, Biologicalen
dc.subjectPiperazines/administration & dosage/*pharmacokineticsen
dc.subjectPolymorphism, Genetic/geneticsen
dc.subjectQuinolones/administration & dosage/*pharmacokineticsen
dc.subjectYoung Adulten
dc.titlePopulation pharmacokinetic modelling of aripiprazole and its active metabolite, dehydroaripiprazole, in psychiatric patientsen
dc.typeArticleen
dc.contributor.AlternativeAuthor김정렬-
dc.contributor.AlternativeAuthor서효범-
dc.contributor.AlternativeAuthor조주연-
dc.contributor.AlternativeAuthor강도형-
dc.contributor.AlternativeAuthor김용구-
dc.contributor.AlternativeAuthor박원명-
dc.contributor.AlternativeAuthor유경상-
dc.contributor.AlternativeAuthor신상구-
dc.contributor.AlternativeAuthor권전수-
dc.contributor.AlternativeAuthor장인진-
dc.identifier.doi10.1111/j.1365-2125.2008.03223.x-
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