Genetic predisposition to oral absorption of imatinib: Correlation of a variant allele in ABCG2 with transport activity

Abstract

3026 Background: Imatinib mesylate (Gleevec, STI-571), an inhibitor of Bcr-abl tyrosine kinase, is currently being used in the treatment of chronic myeloid leukemia and gastrointestinal stromal cell tumors. Interindividual pharmacokinetic variability of imatinib in humans is very substantial, but currently unexplained. Imatinib has recently been shown to be a substrate for ABCG2, a transporter protein that is highly expressed in the intestines and liver, suggesting a major role in drug disposition. A single nucleotide polymorphism (SNP) has been identified in the ABCG2 gene resulting in a non-synonymous mutation (421C>A; Q141K) that causes impaired ability to transport substrates in vitro. Herein, we sought to determine whether patients possessing the mutation would have higher exposure to imatinib. Methods: Patients were treated with oral imatinib at a dose of 100-1000 mg/day. At steady-state, a series of blood samples were drawn to provide a full pharmacokinetic profile over one dosing interval. Imatinib concentrations in plasma were determined by liquid chromatography with tandem mass-spectrometric detection. Pharmacokinetic parameters were calculated by non-compartmental analysis using WinNonlin, and were normalized to total drug dose. Genotyping was carried out using direct sequencing. Results: Of 36 white cancer patients evaluated (23 males, 13 females; median age, 59 years), 32 were wild-type and four were heterozygous for the ABCG2 421C>A SNP (allele frequency, 0.056). No patients with the homozygous variant sequence were identified. The systemic exposure to imatinib, assessed using the area under the curve of imatinib, was approximately 3-fold higher in patients that were heterozygous for the tested SNP compared to patients with the wild-type sequence [mean (± SE), 391 ± 255 versus 136 ± 17.9 ng.h/mL; P = 0.011, t-test]. Conclusions: This pilot study indicates a genetic predisposition to the oral absorption of imatinib, suggesting that patients with low intestinal ABCG2 activity due to ABCG2 421C>A may be at an increased risk for imatinib-induced toxicity. This observation warrants confirmation in a larger patient population involving different ethnic groups. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis