Effects of polymorphisms in NR1I2, CYP3A4, and ABC transporters on the steady-state plasma trough concentrations of bosutinib in Japanese patient with chronic myeloid leukemia

摘要

We investigated the effects of polymorphisms in NR1I2 (7635A G, 8055C T), CYP3A4 (20230G A), ABCB1 (1199G A, 1236C T, 2677G T/A, 3435C T), and ABCG2 (421C A) on the mean plasma trough concentrations (C (0)) of bosutinib at the steady-state in 30 Japanese patients with chronic myeloid leukemia. Bosutinib C (0) values were monitored using high-performance liquid chromatography. The median coefficient of variation (CV) value of the bosutinib C (0) for one patient (intrapatient) during bosutinib therapy was 25.9% (range: 7.66-44.24%). During bosutinib therapy, 17 of 30 patients received 300 mg/day bosutinib. The interpatient CV value for the bosutinib C (0) after administration of 300 mg/day was 45.0%. There were no significant differences in the bosutinib C (0) between genotypes for ABCB1, ABCG2, and CYP3A4 polymorphisms. However, the bosutinib C (0) in patients with the NR1I2 7635G/G or 8055T/T genotype was significantly lower than those in patients with the 7635A allele or 8055C allele, respectively (P = 0.050 and 0.022, respectively). In addition, the bosutinib C (0) in patients with both NR1I2 7635G/G and 8055T/T genotypes was significantly lower than those in patients with other genotypes (P = 0.022). Because patients with the NR1I2 7635G/G or 8055T/T genotype may have increased activity of pregnane X receptor-regulated genes and thereafter higher intestinal expression of CYP3A4 and ABC efflux drug transporters, these patients may have a lower bosutinib C (0). Therefore, information on the NR1I2 genotype may be useful for achieving optimal systemic exposure of bosutinib.