Population Pharmacokinetics and Adverse Events of Erlotinib in Japanese Patients with Non-small-cell Lung Cancer: Impact of Genetic Polymorphisms in Metabolizing Enzymes and Transporters

• Published in: Biological & pharmaceutical bulletin Vol. 41; no. 1; pp. 47 - 56
• Main 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, Hayashi, Mitsuhiro, Kai, Yuki, Saito, Hideyuki, Isobe, Takeshi, Kohrogi, Hirotsugu, Hamada, Akinobu
• Format: Journal Article
• Language: English
• Published: Japan The Pharmaceutical Society of Japan 01.01.2018; Japan Science and Technology Agency
• Subjects: adverse event; Aged; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; ATP-Binding Cassette Transporters - genetics; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; CYP1A2 protein; CYP2D6 protein; Cytochrome P-450 Enzyme System - genetics; Cytochrome P450; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions - epidemiology; Drug-Related Side Effects and Adverse Reactions - etiology; Enzymes; erlotinib; Erlotinib Hydrochloride - adverse effects; Erlotinib Hydrochloride - pharmacokinetics; Erlotinib Hydrochloride - therapeutic use; Exanthema; Female; Gene polymorphism; genetic polymorphism; Genotype & phenotype; Genotypes; Glucuronosyltransferase - genetics; GSTM1 protein; GSTT1 protein; Haplotypes; Humans; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Male; Models, Biological; Pharmacokinetics; Polymorphism, Single Nucleotide; population pharmacokinetics; Prospective Studies; Single-nucleotide polymorphism; Skin; Targeted cancer therapy; adverse event; genetic polymorphism; erlotinib; population pharmacokinetics
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.b17-00521

Determinants of interindividual variability in erlotinib pharmacokinetics (PK) and adverse events remain to be elucidated. This study with 50 Japanese non-small-cell lung cancer patients treated with oral erlotinib at a standard dose of 150 mg aimed to investigate whether genetic polymorphisms affect erlotinib PK and adverse events. Single nucleotide polymorphisms (SNPs) in genes encoding metabolizing enzymes (CYP1A1, CYP1A2, CYP2D6, CYP3A4, CYP3A5, UGT1A1, UGT2B7, GSTM1, and GSTT1) or efflux transporters (ABCB1, and ABCG2) were analyzed as covariates in a population PK model. The ABCB1 1236C>T (rs1128503) polymorphism, not ABCB1*2 haplotype (1236TT–2677TT–3455TT, rs1128503 TT–rs2032582 TT–rs1045642 TT), was a significant covariate for the apparent clearance (CL/F), with the TT genotype showing a 29.4% decrease in CL/F as compared with the CC and the CT genotypes. A marginally higher incidence of adverse events (mainly skin rash) was observed in the TT genotype group; however, patients with high plasma erlotinib exposure did not always experience skin rash. None of the other SNPs affected PK or adverse events. The ABCB1 genotype is a potential predictor for erlotinib adverse events. Erlotinib might be used with careful monitoring of adverse events in patients with ABCB1 polymorphic variants.