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

Abstract

Venetoclax (Ven) and posaconazole (PSZ) are commonly co-administered in patients with hematological diseases, including acute myeloid leukemia, chronic lymphocytic leukemia, and other related conditions. Due to CYP3A inhibition by PSZ, Ven plasma concentrations (ConcVen) are elevated, necessitating dose adjustments. This study aimed to quantitatively characterize the relationship between PSZ exposure and Ven pharmacokinetics through retrospective analysis of data from hematological patients receiving concurrent therapy. We examined correlations between ConcVen (both absolute and normalized by daily dose [ConcVen/DD]) and PSZ exposure metrics (daily dose and plasma concentrations [ConcPSZ]) using Spearman's analysis. A population pharmacokinetic model incorporating an innovative rectified linear unit-like function was developed to quantify the nonlinear interaction between these drugs and characterize Ven disposition, providing a more precise mathematical description of their relationship. This was followed by Monte Carlo simulations to predict steady-state peak concentrations across various dosing scenarios and PSZ exposure concentrations. The analysis included 461 paired Ven-PSZ concentration measurements from 282 patients. Significant correlations were observed between both ConcVen and ConcVen/DD versus ConcPSZ (P < .01). Ven pharmacokinetics was best described by a two-compartment model, with clearance showing significant concentration-dependent reduction with increasing ConcPSZ. Simulations demonstrated that Ven doses of 70 and 100 mg daily maintained therapeutic steady-state concentrations. However, careful monitoring of Ven concentrations is warranted when ConcPSZ exceeds 2.5 µg/mL. Based on these findings, we recommend that Ven dose adjustments during concurrent PSZ therapy be guided by therapeutic drug monitoring of both agents, with dosing decisions informed by our population pharmacokinetic model incorporating measured ConcPSZ.