Clinical Pharmacokinetic Studies of Enzalutamide

Abstract

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.

Trial registration: ClinicalTrials.gov NCT00510718 NCT00974311 NCT01901133 NCT01911715.

Figures

Fig. 1

Structures of enzalutamide, N-desmethyl enzalutamide, and the carboxylic acid metabolite. The asterisk indicates the position of the 14C atom in the radiolabeled molecule that was used in the mass balance and biotransformation study

Fig. 2

Dose-proportionality assessment of enzalutamide for doses ranging from 30 to 360 mg/day. A linear regression (power model) analysis was applied to the mean values for the AUCτ after approximately 3 months of treatment. Circles denote individual patients and the gray area depicts 90 % CIs. AUCτ area under the plasma concentration–time curve during one 24-h dose interval at steady state, CIs confidence intervals

Fig. 3

Mean concentration–time profiles after a single oral dose of 14C-enzalutamide (160 mg, 100 µCi) in the mass balance and biotransformation study (n = 6 healthy adult males)

Fig. 4

Mean cumulative 14C-radioactivity recovery–time profiles after a single oral dose of 14C-enzalutamide (160 mg, 100 µCi) in the mass balance and biotransformation study(n = 6 healthy adult males). The majority of excretion of drug or drug-related product in urine was in the form of carboxylic acid metabolite

Fig. 5

Concentration–time profiles (mean ± standard deviation) for the sum of enzalutamide plus N-desmethyl enzalutamide after a single oral dose of enzalutamide 160 mg in male subjects: a subjects with mild hepatic impairment (Child–Pugh Class A; n = 8) and the age- and BMI-matched control subjects with normal hepatic function (n = 8); b subjects with moderate hepatic impairment (Child–Pugh Class B; n = 6) and the age- and BMI-matched control subjects with normal hepatic function (n = 6). BMI body mass index

Fig. 6

Ctrough versus time profiles for enzalutamide, N-desmethyl enzalutamide, and the carboxylic acid metabolite in an mCRPC patient taking enzalutamide 160 mg/day in the phase III trial (AFFIRM) [2]. Ctrough trough plasma concentration (measured concentration in a predose sample taken directly before the next administration), mCRPC metastatic castration-resistant prostate cancer

Fig. 7

Kaplan–Meier exposure–response analysis for exposure to enzalutamide plus N-desmethyl enzalutamide versus overall survival in the intent-to-treat population in the phase III clinical trial (AFFIRM) [2]. Exposure was based on time‐averaged steady-state predose (Ctrough) plasma concentrations that were classified into quartiles. The analysis involved 1103 patients (n = 176 patients in each of Q1, Q2, Q3, and Q4, and n = 399 placebo patients). Ctrough trough plasma concentration, Q exposure quartile

Fig. 8

Cox proportional hazard model exposure–response analysis for overall survival in the enzalutamide plus N-desmethyl enzalutamide intent-to-treat population. Q exposure quartile