Impact of and Polymorphisms on Imatinib Plasmatic Exposure: An Original Work and Meta-Analysis.

Adequate imatinib plasma levels are necessary to guarantee an efficacious and safe treatment in gastrointestinal stromal tumor (GIST) and chronic myeloid leukemia (CML) patients. Imatinib is a substrate of the drug transporters ATP-binding cassette subfamily B member 1 (ABCB1) and ATP-binding cassette subfamily G member 2 (ABCG2) that can affect its plasma concentration. In the present study, the association between three genetic polymorphisms in (rs1045642, rs2032582, rs1128503) and one in (rs2231142) and the imatinib plasma trough concentration (C) was investigated in 33 GIST patients enrolled in a prospective clinical trial. The results of the study were meta-analyzed with those of other seven studies (including a total of 649 patients) selected from the literature through a systematic review process. The c.421C>A genotype demonstrated, in our cohort of patients, a borderline association with imatinib plasma trough levels that became significant in the meta-analysis. Specifically, homozygous carriers of the c.421 A allele showed higher imatinib plasma C with respect to the CC/CA carriers (C, 1463.2 ng/mL AA, vs. 1196.6 ng/mL CC + AC, = 0.04) in 293 patients eligible for the evaluation of this polymorphism in the meta-analysis. The results remained significant under the additive model. No significant association could be described between polymorphisms and imatinib C, neither in our cohort nor in the meta-analysis. In conclusion, our results and the available literature studies sustain an association between c.421C>A and imatinib plasma C in GIST and CML patients.