Establishment and Application of a Population Pharmacokinetics Model of Venetoclax in Chinese Patients with Hematological Malignancies Based on a Single-center Cohort

OBJECTIVE To establish a population pharmacokinetics(PPK) model of venetoclax in Chinese patients with hematological malignancies based on a single-center cohort, identify covariates that explain the interindividual variability in pharmacokinetics, and provide a scientific basis for the clinical precision medication of venetoclax.

METHODS A total of 122 patients with hematological malignancies who received venetoclax treatment at the First Affiliated Hospital, Zhejiang University School of Medicine from June 2021 to August 2022 were enrolled, and 465 plasma concentration monitoring data points were collected. A nonlinear mixed-effects model was used to construct the PPK model. The effects of covariates, including age, gender, liver function indicators(ALT, AST, ALB), renal function indicators(Scr, BUN, CLcr), and concomitant medications(CYP3A enzyme inducers/inhibitors), on the pharmacokinetic parameters of venetoclax were investigated.

RESULTS The PPK characteristics of venetoclax were consistent with a one-compartment model with first-order absorption and elimination. The typical population apparent clearance(CL/F) of venetoclax was 9.65 L·h⁻¹. Concomitant use of CYP3A enzyme inhibitors, increased ALT levels, and advanced age significantly decreased the CL/F of venetoclax. Model evaluation demonstrated that the established model had good fitting performance, stability, and reliability. Model simulation showed that under the same dosage regimen, the exposure of venetoclax was significantly increased in patients with concomitant use of CYP3A enzyme inhibitors, advanced age, or elevated ALT levels. Furthermore, the results of the external dataset further indicated that the established PPK model had potential clinical applicability.

CONCLUSION A stable and reliable PPK model of venetoclax in Chinese patients with hematological malignancies was successfully established. Concomitant use of CYP3A enzyme inhibitors, advanced age, and elevated ALT levels are key factors that reduce CL/F and increase the exposure of venetoclax. This model can provide a scientific basis for the precision dosage adjustment of venetoclax based on individual patient characteristics.