Pharmacokinetic Drug Interaction Studies with Enzalutamide

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.

Trial registration: ClinicalTrials.gov NCT01911728 NCT01913379.

Figures

Fig. 1

Schematic of the phase I fixed-sequence crossover drug interaction study with CYP2C8, CYP2C9, CYP2C19, and CYP3A4 substrates in patients with metastatic castration-resistant prostate cancer. CYP cytochrome P450. aEnzalutamide placebo-to-match capsules were filled with caprylocaproyl polyoxylglycerides and administered under fasting conditions on days 1 and 5. bPatients were instructed to take enzalutamide (160 mg) on days 13–97 as close to the same time each day as possible; enzalutamide could be taken with or without food, except on days 55 and 62, when it was administered under fasting conditions. cPioglitazone (30 mg) was administered under fasting conditions on days 1 and 55. dThe oral drug cocktail, which consisted of warfarin (10 mg), omeprazole (20 mg), and midazolam (2 mg), was administered under fasting conditions on days 5 and 62

Fig. 2

Mean concentration–time profiles for a enzalutamide, bN-desmethyl enzalutamide, and c carboxylic acid metabolite after a single oral dose of enzalutamide in healthy male subjects. Subjects received enzalutamide alone (n = 13), enzalutamide plus gemfibrozil (strong CYP2C8 inhibitor) (n = 13), and enzalutamide plus itraconazole (strong CYP3A4 inhibitor) (n = 14). Enzalutamide (160 mg) was administered under fasted conditions on day 4. Gemfibrozil (600 mg twice daily) was administered at least 30 min prior to food intake on days 1–21. Itraconazole (200 mg once daily) was administered under fed conditions on days 1–21. CYP cytochrome P450

Fig. 3

Mean plasma concentration–time profiles (n = 14) after single-dose oral administration of CYP substrates alone or in the presence of enzalutamide 160 mg. Insets show data on logarithmic scale. CYP cytochrome P450

Fig. 4

Forest plot summarizing the effects of enzalutamide on exposures to other drugs. AUC area under the plasma concentration–time curve, CI confidence interval, Cmax maximum plasma concentration, CYP cytochrome P450, PK pharmacokinetic parameters