Bayesian Population Model of the Pharmacokinetics of Venetoclax in Combination with Rituximab in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia: Results from the Phase III MURANO Study
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Venetoclax is a selective B-cell lymphoma-2 (BCL-2) inhibitor approved for use as monotherapy or with rituximab in patients with chronic lymphocytic leukemia (CLL). The objectives of the current analysis of observed data from adult patients randomized to venetoclax–rituximab in the phase III MURANO study were to characterize venetoclax pharmacokinetics (PKs) using a Bayesian approach, evaluate whether a previously developed population PK model for venetoclax can describe the PKs of venetoclax when administered with rituximab, and to determine post hoc estimates of PK parameters for the exposure–response analysis.
Parameter estimates and uncertainty estimated by a population PK model were used as priors. Additional covariate effects (CLL risk status, geographic region, and 17p deletion [del(17p)] status) were added to the model. The updated model was used to describe venetoclax PKs after repeated dosing in combination with rituximab, and to determine post hoc estimates of PK parameters for exposure–response analysis.
The PK analysis included 600 quantifiable venetoclax PK samples from 182 patients in the MURANO study. Model evaluation using standard diagnostic plots, visual predictive checks, and normalized prediction distribution error plots indicated no model deficiencies. There was no significant relationship between venetoclax apparent clearance (CL/F) and bodyweight, age, sex, mild and moderate hepatic and renal impairment, or coadministration of weak cytochrome P450 3A inhibitors. The chromosomal abnormality del(17p) and CLL risk status had no apparent effect on the PKs of venetoclax. A minimal increase in venetoclax CL/F (approximately 7%) was observed after coadministration with rituximab. CL/F was 30% lower in patients from Central and Eastern Europe (n = 60) or Asia (n = 4) compared with other regions (95% confidence interval [CI] 21–39%). Apparent central volume of distribution was 30% lower (95% CI 22–38%) in females (n = 56) compared with males (n = 126). No clinically significant impact of region or sex was observed on key safety and efficacy outcomes.
The Bayesian model successfully characterized venetoclax PKs over time and confirmed key covariates affecting PKs in the MURANO study. The model was deemed appropriate for further use in simulations and for generating individual patient PK parameters for subsequent exposure–response evaluation.
Special thanks to the patients and their families, investigators, study coordinators, and support staff, and the MURANO study team members. The authors also thank Dr. Mehrdad Mobasher for his valuable contributions to the manuscript. Venetoclax is being developed in collaboration between Genentech, Inc. and AbbVie. Genentech and AbbVie provided financial support for the study and participated in the design, study conduct, analysis, and interpretation of data, as well as the writing, review, and approval of the manuscript. Third-party medical writing assistance was provided by Christopher Dunn and Andrew Sutton of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd.
Compliance with Ethical Standards
Genentech and AbbVie provided financial support for this study.
Conflict of interest
Rong Deng, Tong Lu, Dan Lu, Chunze Li, Sandhya Girish, Jue Wang, and Dale Miles are employees of Genentech and have equity in Genentech/F. Hoffmann-La Roche Ltd. Leonid Gibiansky received consultancy fees from Genentech. Priya Agarwal and Xiaobin Li are employees of Genentech. Hao Ding and Smita Kshirsagar are paid contractors of Genentech. Michelle Boyer is an employee of F. Hoffmann-La Roche Ltd and has equity in the company. Kathryn Humphrey is an employee of F. Hoffmann-La Roche Ltd. Kevin J. Freise and Ahmed Hamed Salem are employees of AbbVie and have equity in the company. John F. Seymour received grants from AbbVie, Celgene, Janssen, and F. Hoffmann-La Roche Ltd; consultancy fees from AbbVie, Acerta, Celgene, Janssen, F. Hoffmann-La Roche Ltd, and Takeda; travel support from AbbVie; advisory board fees from Celgene; lecture/speakers’ bureau fees from AbbVie and F. Hoffmann-La Roche Ltd; and expert testimony fees from F. Hoffmann-La Roche Ltd. Arnon P. Kater received grants from F. Hoffmann-La Roche Ltd, Genentech, and AbbVie; consultancy fees from AbbVie; travel support from F. Hoffmann-La Roche Ltd; and lecture/speakers’ bureau fees from AbbVie.
All procedures performed in the MURANO study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the MURANO study.
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