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.