Effects of the CYP2D6*10 Allele on the Steady-State Plasma Concentrations of Aripiprazole and Its Active Metabolite, Dehydroaripiprazole, in Japanese Patients With Schizophrenia

Abstract

The CYP2D6*10(*10) allele that causes decreased CYP2D6 activity is present in Asians with a high frequency of approximately 50%. We studied the effects of the *10 allele on the steady-state plasma concentrations of aripiprazole and its active metabolite, dehydroaripiprazole. The subjects were 63 Japanese patients with schizophrenia who had only the wild-type or *10 alleles. Twenty-seven patients were homozygous for the wild-type allele, 31 were heterozygous, and five were homozygous for the *10 allele. All patients had been receiving the fixed doses of aripiprazole for at least 2 weeks. The daily doses were 24 mg (n = 40) and 12 mg (n = 23). No other drugs except biperiden and flunitrazepam were coadministered. Plasma concentrations of aripiprazole and dehydroaripiprazole were measured using liquid chromatography with mass spectrometric detection. The mean ± standard deviation values of concentration/dose ratios of aripiprazole in the patients with zero, one, and two *10 alleles were 9.0 ± 2.9, 12.7 ± 4.4, and 19.0 ± 6.8 ng/mL/mg, respectively, and those values for dehydroaripiprazole were 4.9 ± 1.6, 5.9 ± 1.7, and 5.9 ± 1.9 ng/mL/mg, respectively. The respective values for the sum of aripiprazole and dehydroaripiprazole were 13.9 ± 4.3, 18.6 ± 5.9, and 24.6 ± 8.5 ng/mL/mg. The mean concentration/dose ratios of aripiprazole were significantly (P < 0.01 or P < 0.001) different among the three genotype groups. The values for the sum of aripiprazole and dehydroaripiprazole were significantly higher in patients with one (P < 0.01) and two (P < 0.001) *10 alleles compared with those with zero *10 alleles. This study suggests that the *10 allele plays an important role in controlling the steady-state plasma concentrations of aripiprazole and the sum of aripiprazole and dehydroaripiprazole in Asian subjects.

Aripiprazole augmentation to antidepressant therapy in Japanese patients with major depressive disorder: A randomized, double-blind, placebo-controlled study (ADMIRE study)

“…This is contrary to what was expected but is supported by other successful clinical experiences of low-dose aripiprazole as an adjunctive agent for refractory depression in Asian populations (Chen et al, 2012;Lin et al, 2011;Terao, 2008) but not in Western populations Mischoulon et al, 2012). The CYP2D6 * 10 allele, which decreases CYP2D6 enzyme activity, is known to be highly prevalent in Asian populations but rare in Caucasian populations (Ji et al, 2002); this may affect the pharmacokinetics of aripiprazole in Japanese patients (Suzuki et al, 2011) and impact on treatment response and risk of AEs.…”

The Effectiveness and Safety of Adjunctive Aripiprazole in Taiwanese Patients With Antidepressant-Refractory Major Depressive Disorder

“…33 The range was great, and further study with aripiprazole and placebo is needed. CYP2D6*10 allele was prevalent in Chinese population, 34 and Suzuki et al 35 found that approximately 50% of Asians with the CYP2D6*10 allele showed decreased activity. These might explain our higher remission rate and frequency of adverse effects, but further genetic study of Taiwanese population is clearly needed.…”

Effects of Genetic Polymorphisms of CYP2D6, CYP3A5, and ABCB1 on the Steady-State Plasma Concentrations of Aripiprazole and Its Active Metabolite, Dehydroaripiprazole, in Japanese Patients With Schizophrenia

“…[8][9][10][11][12][13] Several mutated alleles of the CYP2D locus that cause absent enzyme activity, that is, CYP2D6*5 (*5) 14 and CYP2D6*14 (*14) 15 and cause decreased enzyme activity, that is, CYP2D6*10 (*10) 16 have been reported. The steady-state plasma concentrations (Css) of aripiprazole and the sum of aripiprazole and dehydroaripiprazole are significantly dependent on the number of the mutated alleles.…”