Clinical Pharmacokinetic Studies of Enzalutamide.
OBJECTIVE
Oral enzalutamide (160 mg once daily) is approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). This article describes the pharmacokinetics of enzalutamide and its active metabolite N-desmethyl enzalutamide.


METHODS
Results are reported from five clinical studies.


RESULTS
In a dose-escalation study (n = 140), enzalutamide half-life was 5.8 days, steady state was achieved by day 28, accumulation was 8.3-fold, exposure was approximately dose proportional from 30-360 mg/day, and intersubject variability was ≤30 %. In a mass balance study (n = 6), enzalutamide was primarily eliminated by hepatic metabolism. Renal excretion was an insignificant elimination pathway for enzalutamide and N-desmethyl enzalutamide. In a food-effect study (n = 60), food did not have a meaningful effect on area under the plasma concentration-time curve (AUC) of enzalutamide or N-desmethyl enzalutamide, and in an hepatic impairment study, AUC of the sum of enzalutamide plus N-desmethyl enzalutamide was similar in men with mild (n = 6) or moderate (n = 8) impairment (Child-Pugh Class A and B) versus men with normal hepatic function (n = 14). In a phase III trial, an exposure-response analysis of steady-state predose (trough) concentrations (C trough) versus overall survival (n = 1103) showed that active treatment C trough quartiles for 160 mg/day were uniformly beneficial relative to placebo, and no threshold of C trough was associated with a statistically significant better response.


CONCLUSIONS
Enzalutamide has predictable pharmacokinetics, with low intersubject variability. Similar efficacy was observed in patients across the concentration/exposure range associated with a fixed oral dose of enzalutamide 160 mg/day.
Medivation, Inc., 36th Floor, 525 Market Street, San Francisco, CA, 94105, USA. jackie.gibbons@medivation.com.
Jacqueline A
JA
Gibbons
Astellas Pharma Europe B.V., Leiden, The Netherlands.
Taoufik
T
Ouatas
Astellas Pharma Europe B.V., Leiden, The Netherlands.
Walter
W
Krauwinkel
Astellas Pharma Inc., Osaka, Japan.
Yoshiaki
Y
Ohtsu
Astellas Pharma Europe B.V., Leiden, The Netherlands.
Jan-Stefan
JS
van der Walt
ICON Clinical Research, Durham, NC, USA.
Vanessa
V
Beddo
Astellas Pharma Europe B.V., Leiden, The Netherlands.
Michiel
M
de Vries
Medivation, Inc., 36th Floor, 525 Market Street, San Francisco, CA, 94105, USA.
Joyce
J
Mordenti
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D001549:Benzamides; D001711:Biotransformation; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D018565:Food-Drug Interactions; D006801:Humans; D008297:Male; D008875:Middle Aged; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D064129:Prostatic Neoplasms, Castration-Resistant / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism
D000970:Antineoplastic Agents; D001549:Benzamides; D009570:Nitriles; D010669:Phenylthiohydantoin; C540278:enzalutamide