Population Pharmacokinetic Models of Venetoclax in Hematologic Malignancies: A Systematic Review

Abstract

Several population pharmacokinetic (PPK) models of B cell lymphoma-2 (BCL-2) venetoclax (VEN) have been developed and published to characterize the influencing factors of pharmacokinetics in hematologic malignancies. This review described PPK models of VEN examining the magnitude and types of covariate effects in PK parameters, as well as identified areas that require further investigation in order to facilitate their use. Currently, there are six analyses on PPK models of VEN summarized in this review. Most analyses described the pharmacokinetics of VEN with a two-compartment model and all covariates are categorical. The median estimated apparent clearance (CL/F) was 446 L/Day and apparent volume of distribution of the central compartment (V₂/F) was 114.5 L. The median IIV of CL/F reported was 39.5% and V₂/F was 46.7%. Most commonly, CYP3A inhibitors, OATP1B3 inhibitors and rituximab co-administration were found to be significant covariates on CL/F. In addition, sex and population were influential covariates on V₂/F. A detailed description of the characteristics of PPK models of VEN is provided in this review, as well as the effects of covariates on the PK parameters. For future development of the VEN PPK model, CYP3A inhibitors, rituximab co-administration, OATP1B1 transporter inhibitors, sex, population, and food might be considered. Further research and comprehensive investigations should be undertaken to explore reference ranges for therapeutic drug monitoring, define the potential role of patients with cerebrospinal fluid complications, and assess new or potential covariates. These endeavors will facilitate the development of personalized VEN therapy.

Keywords: BCL-2 inhibitor; PPK model; population pharmacokinetics; systematic review; venetoclax.

Figure 1

Study selection process.

Figure 2

The effects of included categorical covariates on CL/F of VEN. The horizontal lines indicate categorical covariate effects (with 95% confidence intervals [CI]). The typical value of clearance in each study was considered to be 1. The effect of each covariate for CL/F is displayed by the ratio of CL/F in the range of each covariate to the typical CL/Fvalue (Data from Jones2016, Deng2019, Gong2023, Samineni2022b19).

Figure 3

The effects of included categorical covariates on V₂/F of VEN. Categorical covariate effects (95% confidence interval [CI]) are represented by open symbols (horizontal lines). The typical value of V₂/F in each study was considered to be 1. The effect of each covariate for V₂/F is displayed by the ratio of V₂/F in the range of each covariate to the typical V₂/F valuee (Data from Jones2016, Deng2019, Gong202316).