Drug Design, Development and Therapy (May 2024)
Population Pharmacokinetic Models of Venetoclax in Hematologic Malignancies: A Systematic Review
Abstract
Yinyu Zhao,1,2 Nan Guo,1,3 Yidan Zhu,1,2 Jingyuan Shang,4 Jiali Chen,1,3 Xingxian Luo,1 Yi Liu,1 Xiaohong Zhang,1 Lin Huang1 1Department of Pharmacy, Peking University People’s Hospital, Beijing, People’s Republic of China; 2School of Pharmaceutical Sciences, Peking University, Beijing, People’s Republic of China; 3School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, People’s Republic of China; 4Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pharmacy, Peking University Cancer Hospital and Institute, Beijing, People’s Republic of ChinaCorrespondence: Xiaohong Zhang; Lin Huang, Department of Pharmacy, Peking University People’s Hospital, No. 11 Xizhimen South Street, Xicheng District, Beijing, 100044, People’s Republic of China, Email [email protected]; [email protected]: 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: venetoclax, BCL-2 inhibitor, population pharmacokinetics, PPK model, systematic review
