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Exposure-Response Analyses of the Effects of Venetoclax, a Selective BCL-2 Inhibitor, on B-Lymphocyte and Total Lymphocyte Counts in Women with Systemic Lupus Erythematosus

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Abstract

Background

Venetoclax is a selective inhibitor of B-cell lymphoma-2, which plays a role in the development of various autoimmune diseases including systemic lupus erythematosus. The aim of these analyses was to quantify the exposure-response relationship for venetoclax effects on B-lymphocyte and total lymphocyte counts as pharmacodynamic markers of efficacy and safety, respectively, in women with systemic lupus erythematosus. The developed modeling framework was also used to evaluate venetoclax effects following cyclic, continuous, or induction/maintenance dosing paradigms as potential dosing alternatives in systemic lupus erythematosus.

Methods

Serial pharmacokinetic and lymphocyte count data from 73 women enrolled in a phase I study of venetoclax (single doses of 10–500 mg or two cycles of 30–600 mg or placebo once daily for 7 days followed by a 21-day washout) were analyzed using a sequential population pharmacokinetic/pharmacodynamic modeling approach. Simulations to evaluate changes in B-lymphocyte and total lymphocyte counts following different venetoclax dosing scenarios were conducted.

Results

Effect of venetoclax plasma exposures on B lymphocytes was described using an indirect linear response model and on total lymphocytes using a maximal response (Emax) with an effect site compartment. Baseline lymphocyte counts were significant covariates on the slope and half maximal inhibitory concentration parameter estimates for the respective models; with higher baseline counts associated with a greater reduction upon treatment with venetoclax. Model simulations showed that continuous dosing with lower doses of venetoclax (e.g., 150 mg daily) are predicted to achieve similar maximal effects on B-lymphocyte counts compared to cyclic dosing with higher doses (e.g., 400 mg 1 week on/3 weeks off); with better recovery of total lymphocyte counts during off-treatment weeks for the cyclic regimens.

Conclusions

Venetoclax treatment in women with systemic lupus erythematosus was associated with exposure-dependent reductions in B lymphocytes, and to a lesser extent, total lymphocyte counts. Results from this study support evaluation of B-cell lymphoma-2 inhibitors as potential therapies for the treatment of systemic lupus erythematosus.

Clinicaltrials.gov

NCT01686555.

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Acknowledgments

Medical writing support was provided by Wesley Wayman, an employee of AbbVie.

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Authors and Affiliations

  1. Clinical Pharmacology and Pharmacometrics, AbbVie Inc., 1 North Waukegan Road, North Chicago, IL, 60064, USA

    Ahmed Nader, Mukul Minocha & Ahmed A. Othman

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  1. Ahmed Nader
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  3. Ahmed A. Othman
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Corresponding author

Correspondence to Ahmed A. Othman.

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Funding

The study was sponsored by AbbVie. AbbVie contributed to the study design, research, and interpretation of data, and the writing, review, and approval of the publication.

Conflict of Interest

Ahmed Nader and Ahmed A. Othman are employees of AbbVie. Mukul Minocha is a former employee of AbbVie. All authors may hold AbbVie stock or stock options.

Ethics Approval

All procedures performed in studies involving human participants 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 standard.

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Informed consent was obtained from all individual participants included in the study.

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Nader, A., Minocha, M. & Othman, A.A. Exposure-Response Analyses of the Effects of Venetoclax, a Selective BCL-2 Inhibitor, on B-Lymphocyte and Total Lymphocyte Counts in Women with Systemic Lupus Erythematosus. Clin Pharmacokinet 59, 335–347 (2020). https://doi.org/10.1007/s40262-019-00818-5

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  • DOI: https://doi.org/10.1007/s40262-019-00818-5

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