Assessment of ethnic differences in pharmacokinetics and clinical responses of acalabrutinib between Chinese and White patients with B-cell malignancies.

Abstract

Aims: The aim of this study was to assess differences between Chinese and White patients in pharmacokinetics (PK) of, and clinical response to, acalabrutinib and its pharmacologically active major metabolite, ACP-5862, to support recommended dosing in Chinese patients with B-cell malignancies.

Methods: A population pharmacokinetic (pop-PK) analysis was conducted to integrate data from a Chinese and a Japanese study into the existing model. The effect of race (East Asian vs. non-East Asian) on acalabrutinib and ACP-5862 PK parameters was assessed. The relationships between model-predicted exposures (e.g., acalabrutinib area under the plasma concentration-time curve for 24 h at steady-state [AUC_24h,ss]) and best overall response and safety outcomes were investigated in Chinese patients and the overall population.

Results: The pop-PK analysis included 686 patients with B-cell malignancies (Chinese, n = 105; Japanese, n = 6). A two-compartment model adequately described the PK profiles of acalabrutinib and ACP-5862 for Chinese patients. East Asian race was a statistically significant covariate on relative bioavailability and apparent volume of the peripheral compartment of acalabrutinib, showing 28% higher PK exposures in Chinese patients. The exposure-efficacy analysis showed that efficacy plateaued in Chinese patients with 100 mg twice-daily dosing while the exposure-safety analysis indicated a flat relationship of acalabrutinib AUC_24h,ss with grade ≥2 or ≥3 adverse events in both Chinese patients and the overall population with 100-400 mg daily doses.

Conclusions: Higher PK exposure was observed in Chinese patients vs. White patients but did not indicate a safety concern based on exposure-response relationships. The results supported using the 100 mg twice-daily dosing regimen in Chinese patients.