Pharmacokinetic Drug Interaction Studies with Enzalutamide.
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Gibbons JA, de Vries M, Krauwinkel W, Ohtsu Y, Noukens J, van der Walt JS, Mol R, Mordenti J, Ouatas T
Pharmacokinetic Drug Interaction Studies with Enzalutamide.
Clin Pharmacokinet. 2015 Oct;54(10):1057-69. doi: 10.1007/s40262-015-0283-1.
- PubMed ID
- 25929560 [ View in PubMed]
- 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 (AUCinfinity) of enzalutamide plus active metabolite by 2.2-fold, and coadministration of itraconazole increased the composite AUCinfinity by 1.3-fold. Enzalutamide did not affect exposure to oral pioglitazone. Enzalutamide reduced the AUCinfinity 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.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Enzalutamide Cytochrome P450 2C19 Protein Humans NoInducerDetails Enzalutamide Cytochrome P450 3A4 Protein Humans NoSubstrateInducerDetails - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareCyclosporineEnzalutamide The serum concentration of Cyclosporine can be decreased when it is combined with Enzalutamide. EnzalutamideGemfibrozil The serum concentration of Enzalutamide can be decreased when it is combined with Gemfibrozil. EnzalutamideRifampicin The serum concentration of Enzalutamide can be decreased when it is combined with Rifampicin.