Pharmacokinetic Drug Interaction Studies with Enzalutamide.
OBJECTIVE
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.
Medivation, Inc., 525 Market Street, 36th Floor, San Francisco, CA, 94105, USA. Jackie.Gibbons@medivation.com.
Jacqueline A
JA
Gibbons
Astellas Pharma Europe B.V., Leiden, The Netherlands.
Michiel
M
de Vries
Astellas Pharma Europe B.V., Leiden, The Netherlands.
Walter
W
Krauwinkel
Astellas Pharma Inc., Osaka, Japan.
Yoshiaki
Y
Ohtsu
Kinesis Pharma B.V., Breda, The Netherlands.
Jan
J
Noukens
Astellas Pharma Europe B.V., Leiden, The Netherlands.
Jan-Stefan
JS
van der Walt
Astellas Pharma Europe B.V., Leiden, The Netherlands.
Roelof
R
Mol
Medivation, Inc., 525 Market Street, 36th Floor, San Francisco, CA, 94105, USA.
Joyce
J
Mordenti
Astellas Pharma Europe B.V., Leiden, The Netherlands.
Taoufik
T
Ouatas
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001549:Benzamides; D018592:Cross-Over Studies; D065687:Cytochrome P-450 CYP2C8 Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D004347:Drug Interactions; D006801:Humans; D008297:Male; D008874:Midazolam / Q000493:pharmacokinetics; D008875:Middle Aged; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*
D001549:Benzamides; D065687:Cytochrome P-450 CYP2C8 Inhibitors; D065692:Cytochrome P-450 CYP3A Inhibitors; D009570:Nitriles; D010669:Phenylthiohydantoin; C540278:enzalutamide; D008874:Midazolam