Imatinib Disposition and ABCB1 (MDR1, P‐Glycoprotein) Genotype

The aim of this study was to explore the impact of individual variation in drug elimination on imatinib disposition. Twenty‐two patients with gastrointestinal stromal tumor or chronic myeloid leukemia initially received imatinib 600 mg daily with dosage subsequently toxicity adjusted. Pharmacokinetic parameters on day 1 and at steady‐state were compared with elimination phenotype and single‐nucleotide polymorphisms of CYP3A5 and ABCB1. A fivefold variation in estimated imatinib clearance (CL/F) was present on day 1 and mean CL/F had fallen by 26% at steady state. This reduction in imatinib CL/F was associated with ABCB1 genotype, being least apparent in thymidine homozygotes at the 1236T>C, 2677G>T/A and 3435C>T loci. Toxicity‐related dose reduction also tended to be less common in these individuals. ABCB1 genotype was associated with steady‐state CL/F due to an apparent genotype‐specific influence of imatinib on elimination. Further evaluation of ABCB1 genotype and imatinib dosage is warranted. Clinical Pharmacology & Therapeutics (2007) 82, 33–40. doi:10.1038/sj.clpt.6100201; published online 9 May 2007