Influence of Itraconazole Co-administration and CYP2D6 Genotype on the Pharmacokinetics of the New Antipsychotic ARIPIPRAZOLE

Abstract

The results of in vitro studies indicated that ARIPIPRAZOLE, a newly developed antipsychotic, is mainly metabolized by the human cytochrome P450 isozymes CYP3A4 and CYP2D6. The objective of the present study was to investigate the influence of itraconazole (hereafter referred to as ITZ) co-administration (CYP3A4 inhibition) on the pharmacokinetics of ARIPIPRAZOLE administered to 24 healthy adult male volunteers in a fasting condition. The influence of CYP3A4 inhibition was also examined by CYP2D6 genotype. All subjects were administered a single oral dose of ARIPIPRAZOLE alone in Period I and a single oral dose of ARIPIPRAZOLE following administration of ITZ at 100 mg/day for 7 consecutive days in Period II. The pharmacokinetic parameters of ARIPIPRAZOLE and its main metabolite OPC-14857 were determined. Co-administration of ITZ increased the Cmax, AUC336 hr, and t1/2,z of ARIPIPRAZOLE and OPC-14857 by 19.4%, 48.0%, and 18.6% and by 18.6%, 38.8%, and 53.4%, respectively. By co-administration of ITZ, the CL/F of ARIPIPRAZOLE in extensive metabolizers was decreased by 26.6%, with an even greater decrease (47.3%) in intermediate metabolizers. For the co-administration period, the CL/F of ARIPIPRAZOLE in intermediate metabolizers was about half of that in extensive metabolizers. For Cmax, there was no significant difference between extensive metabolizers and intermediate metabolizers, and the percent change by co-administration of ITZ was less than 20% in both extensive metabolizers and intermediate metabolizers. For OPC-14857, the t(max) in intermediate metabolizers was longer than that in extensive metabolizers, with the difference being amplified by co-administration of ITZ. The AUC336 hr showed similar increases by co-administration of ITZ in all genotypes. The urinary 6beta-hydroxycortisol/cortisol concentration ratio following ITZ administration for 7 consecutive days was about half of that before the start of ITZ administration, indicating that CYP3A4 metabolic activity was inhibited by administration of ITZ. The influence of CYP3A4 inhibition on the pharmacokinetics of ARIPIPRAZOLE was not considered to be clinically significant. On the other hand, definite differences in pharmacokinetics were observed between CYP2D6 genotypes.

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

“…13,14) Briefly, 68 healthy Japanese male subjects, aged 20-32 years old (mean: 23.1) and weighing 48.2-75.2 kg (mean: 60.7), participated in three clinical trials. Twenty-six subjects participated in the singledose (protocol 1) trial; 15 subjects participated in the multiple-dose (protocol 2) trial; and 27 subjects participated in the itraconazole-coadministration (protocol 3) trial.…”

“…13,14) However, genotyping for CYP3A5 was not performed in the previous studies. 13,14) Table 1 summarizes the genotypes of CYP2D6 in 68 Japanese subjects, who were divided into three groups according to the number of mutant (defective) alleles of 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.…”

“…Genotyping data were also obtained in previous studies, where CYP2D6*2, *4, *5, *10, *14, *18, *36, and *41 were detected by PCR-RFLP and long-PCR methods. 13,14) However, genotyping for CYP3A5 was not performed in the previous studies. 13,14) 15) That is, Group 1 consisted of extensive metabolizers with CYP2D6*1/*1, *1/*2, and *2/*2; Group 2 consisted of subjects with CYP2D6*1/*5, *1/*10, *2/*5, *2/*10, and *2/*41; and Group 3 consisted of subjects with CYP2D6*5/*10, *10/*10, and *41/*41 (Table 1).…”

“…13,14) However, genotyping for CYP3A5 was not performed in the previous studies. 13,14) 15) That is, Group 1 consisted of extensive metabolizers with CYP2D6*1/*1, *1/*2, and *2/*2; Group 2 consisted of subjects with CYP2D6*1/*5, *1/*10, *2/*5, *2/*10, and *2/*41; and Group 3 consisted of subjects with CYP2D6*5/*10, *10/*10, and *41/*41 (Table 1). 15,16) In addition, subjects heterozygous for CYP2D6*2/*41 and homozygous for CYP2D6*41/*41 were classified into Group 2 and Group 3, respectively, since it was reported that the CYP2D6*41 allele may be associated with the intermediate metabolizer phenotype.…”

“…Genotyping data were also obtained in previous studies, where CYP2D6*2, *4, *5, *10, *14, *18, *36, and *41 were detected by PCR-RFLP and long-PCR methods. 13,14) However, genotyping for CYP3A5 was not performed in the previous studies. 13,14) Table 1 summarizes the genotypes of CYP2D6 in 68 Japanese subjects, who were divided into three groups according to the number of mutant (defective) alleles of The population pharmacokinetic parameters of aripiprazole in healthy Japanese males were estimated using a nonlinear mixed effects model (NONMEM) program.…”