Abstract 5459: Association of CYP1A1 and CYP3A5 polymorphisms with pharmacokinetics of erlotinib in patients with non-small cell lung cancer

Abstract

Abstract Background: Erlotinib is a selective inhibitor of EGFR tyrosine kinase activity used for the treatment of patients with NSCLC. It has been reported that ABCB1 polymorphisms affect pharmacokinetics and adverse events of erlotinib in Japanese patients (Hamada A, 2009 AACR meeting). Erlotinib is metabolized by CYP3A4, CYP3A5, CYP1A1, and CYP1A2. The purpose of this study was to investigate the association of CYP1A1 and CYP1A5 single nucleotide polymorphisms (SNPs) with inter-individual variability of erlotinib pharmacokinetics. Methods: Patients with NSCLC were treated with single-agent oral erlotinib 150 mg/day. Plasma levels of erlotinib were measured by high-performance liquid chromatography on days 1 and at steady state (>day 8). DNA was obtained from whole blood, and genotyping was carried out using an Applied Biosystems TaqMan SNP Genotyping Assay on an ABI PRISM® 7900HT system. Results: Fifty patients (mean age, 67 years) were enrolled in the study. Histological classifications were: adenocarcinoma (n=41), squamous cell carcinoma (n=7), and unknown (n=2). Smoking history was indicated as: never smoker (n=23), former smoker (n=24), and current smoker (n=3). For the CYP3A5 6986A>G polymorphism, the frequencies of wild-type (AA), heterozygote (GA), and homozygote (GG) were 6%, 34%, and 60%, respectively. For the CYP1A1 2455A>G polymorphism, the frequencies of wild-type (AA), heterozygote (GA), and homozygote (GG) were 64%, 24%, and 12%, respectively. The mean (±SD) maximum concentrations (Cmax), trough concentrations (Ctrough) on day 1, and steady-state trough concentrations (Css) on >day 8 were 1.66±0.73 μg/mL, 0.77±0.5 μg/mL, and 1.5±0.8 μg/mL, respectively. Lower exposure levels of erlotinib were observed in patients carrying the CYP3A5 6986AA allele than in patients carrying one or two G alleles (GA, GG). The Cmax on day 1 in patients carrying the CYP3A5 AA and GA/GG alleles were 0.76±0.27 μg/mL and 1.78±0.69 μg/mL, respectively. (p=0.0198) On the other hand, patients carrying the CYP1A1 2455GG allele had higher Css than in patients carrying the CYP1A1 2455AA or the CYP1A1 2455GA alleles (2.3±1.16 μg/mL vs. 1.4±0.69 μg/mL, p=0.0161) Conclusion: These results suggested that the CYP3A5 6986A>G and CYP1A1 2455A>G polymorphisms affect the pharmacokinetics of erlotinib in Japanese patients. Further studies involving a larger sample size will be required to evaluate whether measurement of the CYP3A5 and the CYP1A1 polymorphisms may help to optimize erlotinib treatment in individual patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5459. doi:10.1158/1538-7445.AM2011-5459