Role of ADME gene polymorphisms on imatinib disposition: results from a population pharmacokinetic study in chronic myeloid leukaemia.

ABSTRACT

PURPOSE: Imatinib is a substrate of CYP3A4, ABCB1 and ABCG2, and is known to have wide variability in pharmacokinetics (PK). At the same time, a clear relationship between drug levels and response also exists for imatinib in chronic myeloid leukaemia (CML). Therefore, pharmacogenetic-based dosing of imatinib is an attractive proposition. This study aims to characterize the population pharmacokinetics of imatinib in order to identify significant covariates including pharmacogenetic variants. METHODS: Forty-nine patients with CML were enrolled in the study after being on imatinib for at least 4 consecutive weeks. Steady-state pharmacokinetic sampling was performed either in a sparse (4 samples each, n = 44) or intensive manner (9 samples each, n = 5). An additional pharmacogenetic sample was also collected from all patients. Plasma imatinib levels were estimated using a validated HPLC method. Pharmacogenetic variants were identified using the PharmacoScan array platform. Population pharmacokinetic analysis was carried out using NONMEM v7.2. Seven SNPs within CYP3A4, ABCB1 and ABCG2 genes were evaluated for covariate effect on the clearance of imatinib. RESULTS: Imatinib PK was well characterized using a one-compartment model with zero-order absorption. The clearance and volume of distribution were found to be 10.2 L/h and 389 L respectively. Only SNP rs1128503 of the ABCB1 gene had a small but insignificant effect on imatinib clearance, with a 25% reduction in clearance observed in patients carrying the polymorphism. Twenty-three out of forty-nine patients (47%) carried the polymorphic allele, of whom 17 were heterozygous and six were homozygous. CONCLUSION: Our study conclusively proves that genetic polymorphisms in the CYP3A4 and ABC family of transporters do not have any role in the personalized dosing of imatinib in CML.