Pharmacokinetics of Aripiprazole, a New Antipsychotic, following Oral Dosing in Healthy Adult Japanese Volunteers: Influence of CYP2D6 Polymorphism

Abstract

  We investigated the pharmacokinetics (PK) of aripiprazole, a newly developed antipsychotic, and its active metabolite in healthy Japanese, and the influence of CYP2D6 polymorphism on the PK of aripiprazole. Following a single oral 6 mg dose, the mean C_max, t_max, and t_{1/2, z} (terminal phase half life) of aripiprazole were 31.0 ng/mL, 3.6 hr, and 61.0 hr, respectively. The t_{1/2, z} in CYP2D6 IM subjects (75.2 hr) was significantly (p<0.01) longer than that in CYP2D6 EM subjects (45.8 hr), and the systemic clearance of IM subjects was approximately 60% that of EM subjects. The PK in one subject with the CYP2D6^*41 homozygote was similar to that of IM subjects. In repeated oral administration, plasma concentrations of aripiprazole and active metabolite both reached a steady state by Day 14. The half-life of aripiprazole following repeated administration was similar to that following single administration, suggesting that pharmacokinetics was constant during 14-day administration. Our investigations revealed that there is no clear ethnic difference between Japanese and Western subjects in terms of mean plasma PK, while the CYP2D6^*10 allele distinctive to Asian populations influences the PK of aripiprazole. Moreover, our observations suggest that the CYP2D6^*41 allele significantly affects drug-metabolizing activity.