Nonlinear mixed effects model analysis of the pharmacokinetics of aripiprazole in healthy Japanese males.
The population pharmacokinetic parameters of aripiprazole in healthy Japanese males were estimated using a nonlinear mixed effects model (NONMEM) program. Pharmacokinetic data for population analysis were obtained from the single-dose (24 subjects), multiple-dose (15 subjects), and itraconazole-coadministration (27 subjects) trials. The time course of plasma aripiprazole concentration following oral administration was well described by a two-compartment model with first-order input. The mean values of the absorption lag time (ALAG) and absorption rate constant (KA) were estimated to be 0.805 h and 2.65 h(-1), respectively. The mean volume of the central (V(1)/F) and peripheral (V(2)/F) compartment was 3.84 and 1.54 l/kg, respectively, and the mean value of inter-compartment clearance (Q/F) was 0.168 l/h/kg. Oral clearance (CL/F) was estimated to be 0.0645 l/h/kg in the group with CYP2D6*1/*1, *1/*2 and *2/*2. The decrease in CL/F was estimated to be 0.0135 l/h/kg in the group with CYP2D6*1/*5, *1/*10, *2/*5, *2/*10, and *2/*41, and 0.0293 l/h/kg in the group with CYP2D6*5/*10, *10/*10, and *41/*41. The plasma concentration of aripiprazole was increased by coadministration of itraconazole, and the decrease in CL/F was estimated to be 0.0181 l/h/kg.
Koue
Toshiko
T
Department of Clinical Research and Development, Otsuka Pharmaceutical Co. Ltd., Osaka, Japan.
Kubo
Masanori
M
Funaki
Tomoo
T
Fukuda
Tsuyoshi
T
Azuma
Junichi
J
Takaai
Mari
M
Kayano
Yuichiro
Y
Hashimoto
Yukiya
Y
D000284:Administration, Oral; D000328:Adult; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000068180:Aripiprazole; D001499:Bayes Theorem; D001682:Biological Availability; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D017964:Itraconazole / Q000494:pharmacology; D007564:Japan; D008297:Male; D008657:Metabolic Clearance Rate; D008962:Models, Theoretical; D010879:Piperazines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D011110:Polymorphism, Genetic; D015363:Quinolones / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D012984:Software; D013607:Tablets
D014150:Antipsychotic Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D010879:Piperazines; D015363:Quinolones; D013607:Tablets; D017964:Itraconazole; D000068180:Aripiprazole; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human