Abstract
Purpose
Venetoclax, a targeted anticancer agent approved for the treatment of chronic lymphocytic leukemia and acute myeloid leukemia, is a substrate of cytochrome P450 (CYP) 3A enzyme (CYP3A4). Posaconazole, commonly used to prevent invasive fungal infections in neutropenic patients with hematological malignancies, potently inhibits CYP3A4. The purpose of this evaluation was to predict venetoclax exposures following co-administration of posaconazole at doses not previously studied clinically.
Methods
Two physiologically based pharmacokinetic (PBPK) models were developed for posaconazole based on published parameters, one for an oral suspension and another for delayed released tablets. Parameter optimization, guided by sensitivity analyses, was conducted such that the models could replicate clinical exposures of posaconazole and drug–drug interactions with sensitive CYP3A substrates including venetoclax. The clinically verified posaconazole PBPK models were then utilized to predict DDI with a previously published venetoclax PBPK model at clinically relevant dosing scenarios.
Results
The posaconazole PBPK models predicted posaconazole exposure and DDI related fold changes with acceptable prediction errors for both posaconazole formulations. The model predicted exposures of venetoclax, when co-administered with a 300 mg QD dose of delayed release tablets of posaconazole, were in concordance with observed data. Increasing the posaconazole dose to 500 mg QD increased venetoclax exposures by about 12% relative to 300 mg QD, which were still within the venetoclax safe exposure range.
Conclusions
The posaconazole PBPK models were developed and clinically verified. Predictions using the robust PBPK model confirmed the venetoclax label recommendation of 70 mg in the presence of posaconazole at doses up to 500 mg QD.
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Acknowledgements
Medical writing support was provided by Wesley Wayman, an employee of AbbVie.
Funding
The 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 studies and participated in the study design, study conduct, and analysis and interpretation of data and the writing, review, and approval of the manuscript.
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Sumit Bhatnagar, Dwaiypayan Mukherjee, Ahmed Hamed Salem, and Rajeev M. Menon are employees of AbbVie Inc. and may hold AbbVie stock or stock options. John P. Gibbs is a former employee of AbbVie and may hold AbbVie stock or stock options. Dale Miles is an employee of Genentech and may hold stock or stock options.
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Bhatnagar, S., Mukherjee, D., Salem, A.H. et al. Dose adjustment of venetoclax when co-administered with posaconazole: clinical drug–drug interaction predictions using a PBPK approach. Cancer Chemother Pharmacol 87, 465–474 (2021). https://doi.org/10.1007/s00280-020-04179-w
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DOI: https://doi.org/10.1007/s00280-020-04179-w