Pooled Population Pharmacokinetic Analyses of Venetoclax in Patients Across Indications and Healthy Subjects from Phase 1, 2 and 3 Clinical Trials.

Abstract

Following the decade long clinical investigation, venetoclax has accrued PK data across multiple populations and widely-ranging demographics, intrinsic, and extrinsic factors. We leveraged these rich data to systematically characterize venetoclax PK and assess covariate effects with population pharmacokinetic (popPK) modeling. Plasma concentration-time data were pooled from 3016 subjects enrolled in 41 phase 1, 2, and 3 clinical studies, including patients from nine indications and healthy volunteers. A nonlinear mixed-effect model was developed. Covariates were evaluated with full covariate modeling approach. A two-compartment model with three transit absorption compartments described the data well. The impact of moderate and strong CYP3A inhibition on apparent clearance (CL/F), female sex on apparent volume of distribution (V2/F), food effect on relative bioavailability (F1) and dose non-linearity was confirmed. Newly identified covariate effects include 48% lower CL/F in severe hepatic impairment subjects, 61% higher bioavailability in Asian subjects. When multiple CYP3A inhibitors are taken simultaneously, a 49% decrease in CL/F was estimated with multiple moderate inhibitors, more substantial than the 22% decrease of a single moderate inhibitor. An 85% decrease in CL/F was indicated when at least one strong CYP3A inhibitor was taken in combination, comparable to that of a single strong inhibitor. A venetoclax cross-indication popPK model with improved absorption phase characterization was developed. Covariate analyses suggested lower CL/F for severe hepatic impairment subjects and higher bioavailability in Asian subjects. Further decrease in CL/F was indicated when multiple moderate CYP3A inhibitors are present, compared to a single moderate inhibitor. This article is protected by copyright. All rights reserved.