Clinical Pharmacokinetic Studies of Enzalutamide

Abstract

Background and ObjectivesOral 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.MethodsResults are reported from five clinical studies.ResultsIn 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 (Ctrough) versus overall survival (n = 1103) showed that active treatment Ctrough quartiles for 160 mg/day were uniformly beneficial relative to placebo, and no threshold of Ctrough was associated with a statistically significant better response.ConclusionsEnzalutamide 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.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-015-0271-5) contains supplementary material, which is available to authorized users.

Enzalutamide induced acute generalized exanthematous pustulosis

“…The eruptions may have taken longer to heal compared to typical cases of AGEP because of the long half-life of enzalutamide: i.e., 5.8 days. 8 In fact, the time period of the occurrence of new lesions (eighteen days) corresponds to three halflives of enzalutamide, and the four-week time period needed for complete resolution of eruptions corresponds to five half-lives of enzalutamide. According to criteria that assess adverse drug reactions, it was concluded that enzalutamide was responsible for this case of AGEP (suggestive imputation).…”

Development and Validation of a Bioanalytical Method to Quantitate Enzalutamide and its Active Metabolite N-Desmethylenzalutamide in Human Plasma: Application to Clinical Management of Patients With Metastatic Castration–Resistant Prostate Cancer

“…In July 2015, the treating physician decided, in consultation with the clinical pharmacologist, to decrease the dose to 120 mg and to measure plasma concentrations before and after dose reduction. Since no target concentration for efficacy has been identified, the population average concentration of enzalutamide and N-desmethylenzalutamide was used [9]. The average concentrations were divided in quartiles (median Q1–Q4 [19.35–29.65 ug/mL]).…”

“…No difference in overall survival was demonstrated between the quartiles. Plasma concentrations before dose reduction were within the third concentration quartile (Figure 4)[9]. Tiredness and especially complaints regarding malaise improved 1 month after dose reduction.…”

The Role of Drug Exposure in Clinical Development: To What Extent Is Pharmacokinetic Assessment Needed in a Drug Development Programme?

“…Gibbons et al present summary data from multiple studies in this issue, providing a snapshot of exposure to enzalutamide and its key metabolites in healthy volunteers and patients requiring treatment for castration-resistant prostate cancer [2,3]. Exposure data from these key studies aid understanding of how different pieces come together and contribute towards drug approval and, importantly, any dose-related labelling recommendations.…”

“…The study enrolled about 1199 subjects with 2:1 active-to-placebo randomization and documented C min values of enzalutamide and its active metabolite on multiple occasions. The authors failed to establish any C min -survival relationship even with the huge sample size, which was not entirely surprising, given the low pharmacokinetic variability of the drug [2]. Nevertheless, these pharmacokinetic data, along with data collected from the various trials, were integrated with population modelling to evaluate the impact of characteristics such as age, weight, renal or hepatic impairment, and administration with meals on drug exposure.…”