A safety, pharmacokinetic, pharmacogenomic and population pharmacokinetic analysis of the third-generation EGFR TKI, olmutinib (HM61713), after single oral administration in healthy volunteers.

The main objective of this phase I trial was to investigate pharmacokinetics (PKs) of olmutinib in three racial subjects. We also evaluate safety/tolerability and a population PK and pharmacogenomic analysis were performed for explorative purposes. A dose escalation study was conducted in 56 Korean, Japanese and Caucasian subjects. The food effect was assessed in the 300 mg Korean group. Individual PK parameters were calculated by non-compartmental methods and presented by dose and race. Genotype analysis was performed using DMET plus to identify genotypes which affect PK characteristics. A population PK model was developed to explore inter-individual variability and to evaluate the influence of possible covariates using NONMEM . T was 2-3 hour, regardless of race. The mean terminal half-life ranged from 4.8 to 7.4 hour, with no significant differences between dose or racial groups. Dose-normalized C and AUC were not significantly different between race groups. PK parameters were similar between the fasting and fed conditions. A single-nucleotide polymorphism in the GSTM3 gene (rs4783) and a copy number variation in the GSTM1 gene were significantly related to AUC. A one-compartment model with first-order absorption adequately described the observed olmutinib data. Thirty adverse events were observed in 15 subjects, of which 26 events, all mild, were possibly related to olmutinib. A single oral dose of olmutinib 100-300 mg was safe and well tolerated. PK parameters were dose-proportional and did not differ by race. Food intake did not affect olmutinib absorption. Pharmacogenomic analysis indicated that glutathione S-transferase might be involved in olmutinib metabolism.