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

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.