Influence of CYP3A5 and drug transporter polymorphisms on imatinib trough concentration and clinical response among patients with chronic phase chronic myeloid leukemia
- 19 August 2010
- journal article
- Published by Springer Science and Business Media LLC in Journal of Human Genetics
- Vol. 55 (11), 731-737
- https://doi.org/10.1038/jhg.2010.98
Abstract
Imatinib mesylate (IM) trough concentration varies among IM-treated chronic myeloid leukemia (CML) patients. Although IM pharmacokinetics is influenced by several enzymes and transporters, little is known about the role of pharmacogenetic variation in IM metabolism. In this study, associations between IM trough concentration, clinical response and 11 single-nucleotide polymorphisms in genes involved in IM pharmacokinetics (ABCB1, ABCC2, ABCG2 CYP3A5, SLC22A1 and SLCO1B3) were investigated among 67 Japanese chronic phase CML patients. IM trough concentration was significantly higher in patients with a major molecular response than in those without one (P=0.010). No significant correlations between IM trough concentration and age, weight, body mass index or biochemical data were observed. However, the dose-adjusted IM trough concentration was significantly higher in patients with ABCG2 421A than in those with 421C/C (P=0.015). By multivariate regression analysis, only ABCG2 421A was independently predictive of a higher dose-adjusted IM trough concentration (P=0.015). Moreover, previous studies have shown that the ABCG2 421C>A (p.Q141K) variant is prevalent among Japanese and Han Chinese individuals and less common among Africans and Caucasians. Together, these data indicate that plasma IM concentration monitoring and prospective ABCG2 421C>A genotyping may improve the efficacy of IM therapy, particularly among Asian CML patients.Keywords
This publication has 52 references indexed in Scilit:
- Pharmacokinetic/pharmacodynamic correlation and blood-level testing in imatinib therapy for chronic myeloid leukemiaLeukemia, 2009
- Long-term efficacy of imatinib in a practical setting is correlated with imatinib trough concentration that is influenced by body size: a report by the Nagasaki CML Study GroupInternational Journal of Hematology, 2009
- Multicenter prospective trial evaluating the tolerability of imatinib for Japanese patients with chronic myelogenous leukemia in the chronic phase: Does body weight matter?American Journal of Hematology, 2008
- Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia: a subanalysis of the IRIS studyBlood, 2008
- Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemiaBlood, 2006
- Clinical Pharmacokinetics of ImatinibClinical Pharmacokinetics, 2005
- Pharmacokinetic Resistance to Imatinib Mesylate: Role of the ABC Drug Pumps ABCG2 (BCRP) and ABCB1 (MDR1) in the Oral Bioavailability of ImatinibCell Cycle, 2004
- Imatinib mesylate (STI571) is a substrate for the breast cancer resistance protein (BCRP)/ABCG2 drug pumpBlood, 2004
- Single nucleotide polymorphisms and haplotype frequencies ofCYP3A5 in a Japanese populationHuman Mutation, 2003
- Efficacy and Safety of a Specific Inhibitor of the BCR-ABL Tyrosine Kinase in Chronic Myeloid LeukemiaNew England Journal of Medicine, 2001