Quantifying the Effect of Posaconazole on Venetoclax Metabolism in Chinese Patients with Hematological Diseases

INTRODUCTION Venetoclax, a BCL-2 inhibitor, has significantly advanced the treatment of hematologic diseases like chronic lymphocytic leukemia(CLL), small lymphocytic lymphoma (SLL), and acute myeloid leukemia(AML), resulting in improved survival rates. However, its clinical use is complicated by serious adverse events like tumor lysis syndrome, neutropenia, and thrombocytopenia, as well as a highly variable pharmacokinetic profile with a 15-fold variation in oral clearance and the risk of drug-drug interactions (DDIs) that may exacerbate side effects. Venetoclax is primarily metabolized by cytochrome CYP3A4, which can be affected by concomitant medications such as posaconazole. AIM This study aims to establish a detailed pharmacokinetic model to quantify the interaction between venetoclax and posaconazole, enhance our understanding of their interaction, and predict drug concentrations to support rational clinical use. METHODS This retrospective study was conducted from January 2022 to December 2023 and included patients with hematologic diseases treated with venetoclax and posaconazole at Hebei Yanda Lu Daopei Hospital. Drug concentrations were determined using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). A population pharmacokinetic model was developed using a nonlinear mixed-effects model (two-compartment model), with covariates including gender, age, body weight, liver and kidney function test results, complete blood count, and posaconazole concentrations within 3 days around venetoclax blood sampling, incorporated through a stepwise approach. The models's stability was assessed using the bootstrap method. A simulation with 1000 subjects was then performed using the final PK model to simulate venetoclax concentrations for different dose regimens and different posaconazole concentrations. RESULTS The study included pharmacokinetic data from 229 patients, encompassing 389 pairs of venetoclax and posaconazole concentrations derived from therapeutic drug monitoring (TDM) data. Through forward selection and recursive backward elimination, posaconazole concentration and aspartate transaminase (AST) were identified as significant covariates for the clearance parameter (CL), resulting in a reduction in the objective function value (OFV) by 188.7. The final population pharmacokinetic model's performance was evaluated using goodness-of-fit (GOF) plots. Observations versus individual predicted values (IPRED) in the final model were evenly distributed across the line of identity. All conditional weighted residual values (CWRES) were within the range from -5 to 5, indicating a good model fit. Simulation results indicated that posaconazole concentration significantly increases venetoclax concentration, with a 2.5 μg/mL posaconazole level capable of doubling venetoclax plasma concentration. The mean venetoclax concentration exhibits a linear increase with dose increment, while inter-individual variability in these concentrations was also observed. CONCLUSIONS A quantitative relationship between posaconazole and venetoclax concentrations was established. AST was also identified as an important factor affecting venetoclax plasma concentrations. Simulation results suggest that when posaconazole concentrations reach 2.5 μg/mL, the venetoclax dose should be halved. Due to increased variability in individualized concentrations, TDM should be employed to ensure medication safety for patients receiving a 400 mg dose of venetoclax. Continuous monitoring of both venetoclax and posaconazole plasma concentrations is necessary for patients with hematologic diseases.