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Impact of ritonavir dose and schedule on CYP3A inhibition and venetoclax clinical pharmacokinetics

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Abstract

Purpose

Venetoclax is a selective BCL-2 inhibitor indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). It is predominately metabolized by cytochrome P450 (CYP) 3A. The study objective was to determine the effect of different dosage regimens of ritonavir, a strong CYP3A inhibitor, on the pharmacokinetics of venetoclax in 20 healthy subjects.

Methods

In cohorts 1 and 2, subjects received single 10 mg doses of venetoclax in periods 1 and 2 and a single 50- or 100-mg dose of ritonavir in period 2. In cohort 3, subjects received 10-mg venetoclax doses on day 1 of period 1 and days 1 and 11 of period 2, and 50 mg ritonavir daily on days 1 to 14 of period 2.

Results

Single doses of 50 and 100 mg ritonavir increased the venetoclax maximum concentration (Cmax) 2.3- to 2.4-fold compared to venetoclax alone and the area under the curve (AUC) 6.1- and 8.1-fold, respectively. Daily 50 mg ritonavir resulted in a 2.4- and 7.9-fold increase in venetoclax Cmax and AUC, respectively. Administration of 50 mg ritonavir daily saturated CYP3A inhibition and completely inhibited the formation of the major venetoclax metabolite M27. Time-dependent CYP3A inhibition with daily 50 mg ritonavir was offset by ritonavir CYP3A induction, resulting in a limited net increase in CYP3A inhibition with multiple doses.

Conclusion

After completion of the dose ramp-up, venetoclax dose reductions of at least 75% are recommended when administered concomitantly with strong CYP3A inhibitors to maintain venetoclax exposures within the established therapeutic window for CLL treatment.

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Acknowledgements

Venetoclax (ABT-199/GDC-0199) is being developed in collaboration between AbbVie and Genentech. We thank the subjects who participated in this trial and their families; the study coordinators and the support staff at the clinical site; and AbbVie and Genentech venetoclax team members.

This study was supported by AbbVie in collaboration with Genentech/Roche. AbbVie and Genentech provided financial support for the study and participated in the design, study conduct, and analysis and interpretation of data as well as the writing, review, and approval of the manuscript. Medical writing support was provided by Therese Stickler, a freelance writer under contract with AbbVie, and Allison Kitten, an employee of AbbVie. Kevin J. Freise, Beibei Hu, and Ahmed Hamed Salem are employees of AbbVie and may hold AbbVie stock or stock options.

Funding

This study was supported by AbbVie in collaboration with Genentech/Roche. Venetoclax (ABT-199/GDC-0199) is being developed in collaboration between AbbVie and Genentech. AbbVie and Genentech provided financial support for the study and participated in the design, study conduct, and analysis and interpretation of data as well as the writing, review, and approval of the manuscript.

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Authors and Affiliations

  1. AbbVie Inc., 1 North Waukegan Road, North Chicago, IL, 60064, USA

    Kevin J. Freise, Beibei Hu & Ahmed Hamed Salem

  2. Department of Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt

    Ahmed Hamed Salem

Authors
  1. Kevin J. Freise
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  2. Beibei Hu
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  3. Ahmed Hamed Salem
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Contributions

KJF, BH, and AHS contributed to the study design, data analysis, interpreting of results, writing the manuscript, and approving the final version.

Corresponding author

Correspondence to Ahmed Hamed Salem.

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Research involving human participants

The study was performed in accordance with the protocol, International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines, 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 study.

Conflict of interest

Kevin J. Freise, Beibei Hu, and Ahmed Hamed Salem are employees of AbbVie and may hold AbbVie stock or stock options.

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Freise, K.J., Hu, B. & Salem, A.H. Impact of ritonavir dose and schedule on CYP3A inhibition and venetoclax clinical pharmacokinetics. Eur J Clin Pharmacol 74, 413–421 (2018). https://doi.org/10.1007/s00228-017-2403-3

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