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Published on: May 27, 2021
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Pharmacokinetic Drug Interaction Studies with Enzalutamide
Jacqueline A Gibbons1, Michiel de Vries2, Walter Krauwinkel2
1Medivation, Inc., 525 Market Street, 36th Floor, San Francisco, CA, 94105, USA. Jackie.Gibbons@medivation.com.
Clinical Pharmacokinetics
|May 2, 2015
Summary
Enzalutamide drug interactions were studied. Coadministration with CYP2C8 inhibitors requires dose reduction, while use with CYP2C9, CYP2C19, or CYP3A4 substrates should be avoided due to altered enzalutamide exposure.
Area of Science:
- Pharmacology
- Drug Metabolism
- Oncology
Background:
- Enzalutamide is approved for metastatic castration-resistant prostate cancer (mCRPC).
- Understanding enzalutamide's drug interactions is crucial for safe and effective treatment.
Purpose of the Study:
- To evaluate drug interactions between oral enzalutamide and inhibitors/substrates of key cytochrome P450 enzymes.
- To determine the impact of CYP2C8, CYP2C9, CYP2C19, and CYP3A4 modulators on enzalutamide pharmacokinetics.
Main Methods:
- Phase I, parallel-treatment and crossover design studies.
- Assessed pharmacokinetics of enzalutamide and its metabolite with CYP inhibitors (gemfibrozil, itraconazole).
- Evaluated enzalutamide's effect on CYP substrates (pioglitazone, warfarin, omeprazole, midazolam).
Main Results:
- Strong CYP2C8 inhibition (gemfibrozil) increased enzalutamide exposure 2.2-fold; CYP3A4 inhibition (itraconazole) increased it 1.3-fold.
- Enzalutamide is a moderate inducer of CYP2C9 and CYP2C19, and a strong inducer of CYP3A4.
- Enzalutamide decreased exposure to S-warfarin, omeprazole, and midazolam by 56%, 70%, and 86% respectively.
Conclusions:
- Reduce enzalutamide dose to 80 mg/day if coadministered with a strong CYP2C8 inhibitor.
- Avoid concomitant use of enzalutamide with drugs metabolized by CYP2C9, CYP2C19, or CYP3A4, especially those with a narrow therapeutic index.
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