title: Population pharmacokinetic modelling of aripiprazole and its active metabolite, dehydroaripiprazole, in psychiatric patients.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Jung-Ryul
authors.initials: JR
authors.lastname: Kim
authors.forename: Hyo-Bum
authors.initials: HB
authors.lastname: Seo
authors.forename: Joo-Youn
authors.initials: JY
authors.lastname: Cho
authors.forename: Do-Hyung
authors.initials: DH
authors.lastname: Kang
authors.forename: Yong Ku
authors.initials: YK
authors.lastname: Kim
authors.forename: Won-Myong
authors.initials: WM
authors.lastname: Bahk
authors.forename: Kyung-Sang
authors.initials: KS
authors.lastname: Yu
authors.forename: Sang-Goo
authors.initials: SG
authors.lastname: Shin
authors.forename: Jun Soo
authors.initials: JS
authors.lastname: Kwon
authors.forename: In-Jin
authors.initials: IJ
authors.lastname: Jang
mesh_terms: D000293:Adolescent; D000328:Adult; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000068180:Aripiprazole; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000493:pharmacokinetics; D004347:Drug Interactions / Q000235:genetics; D016903:Drug Monitoring; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D001523:Mental Disorders / Q000188:drug therapy*; D008657:Metabolic Clearance Rate / Q000235:genetics; D008875:Middle Aged; D008954:Models, Biological; D010879:Piperazines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011110:Polymorphism, Genetic / Q000235:genetics; D015363:Quinolones / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D010879:Piperazines; D015363:Quinolones; C517414:dehydroaripiprazole; D000068180:Aripiprazole; D019389:Cytochrome P-450 CYP2D6