Kumamoto University Hospital, Kumamoto, Japan
Sho Saeki , Jiichiro Sasaki , Norihiro Iwamoto , Megumi Inaba , Sunao Ushijima , Hiroto Kishi , Shinji Fujii , Hiroshi Semba , Kosuke Kashiwabara , Shinya Sakata , Yuki Kai , Yukari Tsubata , Takeshi Isobe , Chihiro Endo-Tsukude , Hirotsugu Kohrogi , Hideyuki Saito , Akinobu Hamada
Background: Erlotinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, which has been shown to be effective in non-small cell lung cancer (NSCLC) patients. Several population pharmacokinetics (PK) analyses have reported large inter-individual variabilities in erlotinib blood exposure and its toxicities. Here, aiming to develop a optimal dose regimen, we analyzed single nucleotide polymorphisms (SNPs) of PK-related genes and investigated the relationships between genotypes and inter-individual 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. 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: A 2-compartment model with first order absorption and linear elimination described the erlotinib PK. Only the ABCB1 1236C > T polymorphism was a statistically 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 inter-individual 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 > T influenced the exposure of erlotinib. 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.
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