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Pharmacokinetic Drug Interaction Studies with Enzalutamide. | LitMetric

AI Article Synopsis

  • Two phase I studies were conducted to understand how enzalutamide, a drug for advanced prostate cancer, interacts with other medications, focusing on its metabolism through specific liver enzymes.
  • The studies found that taking gemfibrozil (a CYP2C8 inhibitor) significantly raised enzalutamide levels, while itraconazole (a CYP3A4 inhibitor) also increased levels but to a lesser extent; however, enzalutamide decreased levels of several other drugs processed by different enzymes, indicating it can affect their effectiveness.
  • The study concluded that if enzalutamide is combined with a strong CYP2C8 inhibitor, its dose should be reduced to 80 mg/day, and it's best to avoid simultaneous use with

Article Abstract

Background And Objectives: Two phase I drug interaction studies were performed with oral enzalutamide, which is approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC).

Methods: A parallel-treatment design (n = 41) was used to evaluate the effects of a strong cytochrome P450 (CYP) 2C8 inhibitor (oral gemfibrozil 600 mg twice daily) or strong CYP3A4 inhibitor (oral itraconazole 200 mg once daily) on the pharmacokinetics of enzalutamide and its active metabolite N-desmethyl enzalutamide after a single dose of enzalutamide (160 mg). A single-sequence crossover design (n = 14) was used to determine the effects of enzalutamide 160 mg/day on the pharmacokinetics of a single oral dose of sensitive substrates for CYP2C8 (pioglitazone 30 mg), CYP2C9 (warfarin 10 mg), CYP2C19 (omeprazole 20 mg), or CYP3A4 (midazolam 2 mg).

Results: Coadministration of gemfibrozil increased the composite area under the plasma concentration-time curve from time zero to infinity (AUC∞) of enzalutamide plus active metabolite by 2.2-fold, and coadministration of itraconazole increased the composite AUC∞ by 1.3-fold. Enzalutamide did not affect exposure to oral pioglitazone. Enzalutamide reduced the AUC∞ of oral S-warfarin, omeprazole, and midazolam by 56, 70, and 86 %, respectively; therefore, enzalutamide is a moderate inducer of CYP2C9 and CYP2C19 and a strong inducer of CYP3A4.

Conclusions: If a patient requires coadministration of a strong CYP2C8 inhibitor with enzalutamide, then the enzalutamide dose should be reduced to 80 mg/day. It is recommended to avoid concomitant use of enzalutamide with narrow therapeutic index drugs metabolized by CYP2C9, CYP2C19, or CYP3A4, as enzalutamide may decrease their exposure.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4580724PMC
http://dx.doi.org/10.1007/s40262-015-0283-1DOI Listing

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