Improved Characterization of the Pharmacokinetics of Acalabrutinib and its Pharmacologically Active Metabolite, ACP-5862, in Patients With B-Cell Malignancies and in Healthy Subjects Using a Population Pharmacokinetic Approach.

This analysis aimed to describe the pharmacokinetics (PK) of acalabrutinib and its active metabolite, ACP-5862. A total of 8935 acalabrutinib samples from 712 subjects and 2394 ACP-5862 samples from 304 subjects from 12 clinical studies in patients with B-cell malignancies and healthy subjects were analyzed by non-linear mixed-effects modelling. Acalabrutinib PK was characterized by a two-compartment model with first-order elimination. The large variability in absorption was adequately described by transit compartment chain and first-order absorption, with between-occasion variability on the mean transit time and relative bioavailability. The PK of ACP-5862 was characterized by a two-compartment model with first-order elimination, and the formation rate was defined as the acalabrutinib clearance multiplied by the fraction metabolized. Health status, Eastern Cooperative Oncology Group performance status, and co-administration of proton pump inhibitors were significant covariates. However, none of the investigated covariates led to clinically meaningful changes in exposure, supporting a flat dosing of acalabrutinib.