Clinical Pharmacokinetic Studies of Enzalutamide

Background and Objectives 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...

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Bibliographic Details
Published in:Clinical pharmacokinetics 2015-10, Vol.54 (10), p.1043-1055
Main Authors: Gibbons, Jacqueline A., Ouatas, Taoufik, Krauwinkel, Walter, Ohtsu, Yoshiaki, van der Walt, Jan-Stefan, Beddo, Vanessa, de Vries, Michiel, Mordenti, Joyce
Format: Article
Language:English
Subjects:
Adult
Aged
Aged, 80 and over
Antineoplastic Agents - administration & dosage
Antineoplastic Agents - blood
Antineoplastic Agents - pharmacokinetics
Biotransformation
Dose-Response Relationship, Drug
Drug Administration Schedule
Food-Drug Interactions
Humans
Internal Medicine
Male
Medicine
Medicine & Public Health
Middle Aged
Original
Original Research Article
Pharmacology/Toxicology
Pharmacotherapy
Phenylthiohydantoin - administration & dosage
Phenylthiohydantoin - analogs & derivatives
Phenylthiohydantoin - blood
Phenylthiohydantoin - pharmacokinetics
Prostatic Neoplasms, Castration-Resistant - blood
Prostatic Neoplasms, Castration-Resistant - drug therapy
Prostatic Neoplasms, Castration-Resistant - metabolism
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Summary:Background and Objectives 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.
ISSN:0312-5963
1179-1926
DOI:10.1007/s40262-015-0271-5