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

AbstractWe investigated the effects of polymorphisms inNR1I2 (7635A>G, 8055C>T),CYP3A4 (20230G>A),ABCB1 (1199G>A, 1236C>T, 2677G>T/A, 3435C>T), andABCG2 (421C>A) on the mean plasma trough concentrations (C0) of bosutinib at the steady-state in 30 Japanese patients with chronic myeloid leukemia. BosutinibC0 values were monitored using high-performance liquid chromatography. The median coefficient of variation (CV) value of the bosutinibC0 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 bosutinibC0 after administration of 300  mg/day was 45.0%. There were no significant differences in the bosutinibC0 between genotypes forABCB1, ABCG2, andCYP3A4 polymorphisms. However, the bosutinibC0 in patients with theNR1I2 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 bosutinibC0 in patients with bothNR1I2 7635G/G and 8055T/T genotypes was significantly lower than those in patients with other genotypes (P = 0.022). Because patients with theNR1I2 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 bosutinibC0. Therefo...
Source: Medical Oncology - Category: Cancer & Oncology Source Type: research