Abstract 5481: Effect of genetic polymorphisms on erlotinib pharmacokinetics and toxicity in Japanese patients with non-small-cell lung cancer
Authors: Endo-Tsukude Chihiro , Sasaki Ji-ichiro , Saeki Sho , Iwamoto Norihiro , Inaba Megumi , Ushijima Sunao , Kishi Hiroto , Fujii Shinji , Semba Hiroshi , Kashiwabara Kosuke , Tsubata Yukari , Kai Yuki , Saito Hideyuki , Isobe Takeshi , Kohrogi Hirotsugu , Hamada Akinobu 
Published: August 2015

Abstract
Introduction: Erlotinib is an epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor, a 150 mg daily dose of which has been shown to be effective for improving overall survival in non-small-cell lung cancer (NSCLC) patients who had failed at least 1 prior chemotherapy regimen. Furthermore, erlotinib demonstrated significant prolongation of progression-free survival versus standard chemotherapy in EGFR mutation positive NSCLC patients. However, skin rash and diarrhea often occurs, and these toxicities lead to discontinuation of therapy or dose reduction in many patients. Several population pharmacokinetics (PK) analyses have reported large interindividual variabilities in erlotinib blood exposure and its toxicities. However, none of those analyses clearly explains the determinants of these large interindividual variabilities. Here, aiming to develop a dose regimen that would maintain the clinical benefits of erlotinib while minimizing its adverse effects, we analyzed single nucleotide polymorphisms (SNPs) of PK-related genes and investigated the relationships between genotypes and interindividual variabilities in the PK and adverse effects.
Methods: We performed a multicenter study of 50 patients treated with 150 mg erlotinib as a second-line or later treatment. PK and toxicity were assessed. For PK analyses, blood samples were collected from 28 patients at 5 to 18 time points, and trough blood samples were collected from 20 patients at 1 time point. SNPs in genes encoding metabolizing enzymes or efflux transporters (CYP1A1, CYP1A2, CYP2D6, CYP3A4, CYP3A5, UGT1A1, UGT2B7, GSTM1, GSTT1, ABCB1, and ABCG2) were analyzed. Population PK analyses were carried out using NONMEM. SNPs were tested as covariates in a population PK model. The effects of these SNPs and erlotinib exposure on toxicity were evaluated.
Results and Discussion: A 2-compartment model with first order absorption and linear elimination described the erlotinib PK. Only the ABCB1 1236C&gt;T polymorphism was a statically significant covariate for CL/F, showing a 29.4% decrease in CL/F for the TT genotype as compared with the CC and the CT genotypes. The interindividual variability in CL/F decreased by 10.6% after inclusion of the TT genotype as a covariate in the model. This result indicates that a dose reduction to 100 mg for the TT genotype group could equalize the erlotinib exposure between each genotype group. A higher incidence of adverse effects (mainly diarrhea) was observed in the TT genotype group.
Conclusions: Of the 20 SNPs that are related to erlotinib PK, only ABCB1 1236C&gt;T influenced the exposure of erlotinib. This SNP was suggested to be related to the risk of adverse events. Individual dosing based on ABCB1 genotype might reduce the adverse effects. Further clinical trials are needed to investigate the toxicity and the clinical outcome of this dose regimen.
Citation Format: Chihiro Endo-Tsukude, Ji-ichiro Sasaki, Sho Saeki, Norihiro Iwamoto, Megumi Inaba, Sunao Ushijima, Hiroto Kishi, Shinji Fujii, Hiroshi Semba, Kosuke Kashiwabara, Yukari Tsubata, Yuki Kai, Hideyuki Saito, Takeshi Isobe, Hirotsugu Kohrogi, Akinobu Hamada. Effect of genetic polymorphisms on erlotinib pharmacokinetics and toxicity in Japanese patients with non-small-cell lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5481. doi:10.1158/1538-7445.AM2015-5481