Tucatinib is a highly selective human epidermal growth factor receptor 2 (HER2) -directed tyrosine kinase inhibitor approved in multiple countries for metastatic HER2-positive breast cancer and in the US for metastatic HER2-postive metastatic colorectal cancer. This phase Ⅰ study (N＝36) compared the pharmacokinetic (PK) and safety profiles of tucatinib administered at 50-, 150-, and 300-mg doses taken twice daily orally in healthy Japanese (n＝18［n＝6 per tucatinib dose cohort］) and Caucasian volunteers (n＝18［n＝6 per tucatinib dose cohort］) to assess ethnicity effects on PK and dose proportionality of tucatinib. Ethnicity effects between both populations were evaluated using an analysis of covariance (ANCOVA) model and dose proportionality of tucatinib was assessed using a log-transformed linear regression model. Tucatinib steady-state exposure (AUC_ss) and maximum plasma concentration (C_max) geometric mean values were similar between Japanese and Caucasian volunteers, with ANCOVA-adjusted geometric mean ratios (90％ confidence intervals) of 2.63 (1.04, 6.62), 1.11 (0.76, 1.62), and 1.33 (0.91, 1.95) for C_max and 1.97 (0.85, 4.56), 1.05 (0.70, 1.58), and 1.04 (0.72, 1.49) for AUC_ss in the tucatinib 50-, 150-, and 300-mg cohorts, respectively. Thirty-three treatment-emergent adverse events (TEAEs) in 13 Caucasian volunteers and 2 TEAEs in 2 Japanese volunteers were reported. All TEAEs were grade 1, and the majority resolved by the end of study. At the approved therapeutic dose of 300 mg twice daily, tucatinib had a manageable safety profile and exposures were similar between Japanese and Caucasian volunteers. These findings indicate there is no need for dose alteration of tucatinib based on ethnicity.

Objective: To assess the safety, tolerability, and pharmacokinetics of belumosudil, a selective Rho-associated coiled-coil-containing protein kinase 2 inhibitor, in healthy Japanese male adults, a phase Ⅰ, randomized, double-blind, placebo-controlled trial was conducted.

Methods: In the single-dose study, 200, 400, or 800 mg of belumosudil or matching placebo was orally administered to 3 separate cohorts. In the multiple-dose study, 200 mg once daily, 200 mg twice daily, or 400 mg once daily of belumosudil or placebo was orally administered for 7 days to 3 separate cohorts. In each cohort, 8 participants were randomly assigned in a 3：1 ratio to receive belumosudil or placebo.

Results: In each cohort of the single-dose and multiple-dose studies, 6 participants received belumosudil and 2 received placebo. All participants completed the study. In the single-dose study, the increases in C_max and AUC were almost linear between the doses of 200 and 400 mg, but were lower than dose-proportional at 800 mg. In the multiple-dose study, t_max and t_1/2 on Day 7 were similar to those after single-dose administration, irrespective of the dosage regimen. C_max and AUC increased as the dose increased. Accumulation of belumosudil after multiple administrations was minimal. In the single-dose and multiple-dose studies, 2 and 5 participants receiving belumosudil experienced adverse events, respectively. All adverse events were mild in severity, and no event led to study discontinuation.

Conclusion: The pharmacokinetic profiles of belumosudil in these studies were similar to those obtained from healthy volunteers in western countries. Belumosudil was well tolerated in both studies.