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

Effects of polymorphisms in NR1I2, CYP3A4, and ABC transporters on the steady-state plasma trough... 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Medical Oncology Springer Journals

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

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Publisher
Springer US
Copyright
Copyright © 2018 by Springer Science+Business Media, LLC, part of Springer Nature
Subject
Medicine & Public Health; Oncology; Hematology; Pathology; Internal Medicine
ISSN
1357-0560
eISSN
1559-131X
D.O.I.
10.1007/s12032-018-1146-z
Publisher site
See Article on Publisher Site

Abstract

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.

Journal

Medical OncologySpringer Journals

Published: May 7, 2018

References

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