Nonlinear Mixed Effects Model Analysis of the Pharmacokinetics of Aripiprazole in Healthy Japanese Males

Abstract

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.