Journal Article

Clinical Pharmacokinetic Studies of Enzalutamide

Ohtsu, Yoshiaki, van der Walt, Jan-Stefan, de Vries, Michiel, Mordenti, Joyce, Gibbons, Jacqueline A., Krauwinkel, Walter, Beddo, Vanessa, Ouatas, Taoufik

2015

Overview

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.

• Publisher: Springer International Publishing,Springer Nature B.V
• Subject: 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