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A comparison of the pharmacokinetics and safety of enzalutamide in subjects with hepatic impairment and matched healthy subjects
Author(s) -
Krauwinkel W.,
Noukens J.,
Dijk J.,
Popa S.,
Ouatas T.,
Vries M.,
Phung D.,
Gibbons J.,
Mordenti J.,
Mateva L.
Publication year - 2017
Publication title -
journal of clinical pharmacy and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.622
H-Index - 73
eISSN - 1365-2710
pISSN - 0269-4727
DOI - 10.1111/jcpt.12503
Subject(s) - enzalutamide , pharmacokinetics , medicine , gastroenterology , prostate cancer , active metabolite , pharmacology , cancer , androgen receptor
Summary What is known and objective Enzalutamide is an androgen receptor inhibitor approved for treatment of metastatic castration‐resistant prostate cancer. Enzalutamide is highly protein bound and eliminated primarily by hepatic metabolism; therefore, it is important to understand whether enzalutamide pharmacokinetics is altered by hepatic impairment. Methods Pharmacokinetic data were obtained from two non‐randomized, open‐label, single‐dose, phase 1 studies conducted in patients with mild (Child‐Pugh class A, n = 6) or moderate (Child‐Pugh class B, n = 8) hepatic impairment ( NCT 01901133) or severe (Child‐Pugh class C, n = 8) hepatic impairment ( NCT 02138162) and their corresponding matched healthy controls; data from both studies are presented here. Subjects with hepatic impairment had liver cirrhosis ( n = 19) or chronic hepatitis ( n = 3). All subjects received a single oral dose of 160 mg enzalutamide under fasting conditions, with blood samples collected predose and up to 49 days post‐dose. Results and discussion Exposure to enzalutamide active moieties, based on the area under the curve of the sum of enzalutamide and N ‐ desmethyl enzalutamide (an active metabolite with similar potency to enzalutamide), increased by 13%, 18% and 4% in subjects with mild, moderate and severe hepatic impairment, respectively, relative to matched controls. Compared with healthy controls, the mean maximum plasma concentration for enzalutamide active moieties was 24% higher in subjects with mild hepatic impairment and 11% and 41% lower in subjects with moderate and severe hepatic impairment, respectively. Enzalutamide was generally well tolerated, with no clinically significant trends in abnormal laboratory findings, vital signs or electrocardiograms. What is new and conclusions No major differences in single‐dose pharmacokinetics were observed in subjects with hepatic impairment vs. matched healthy controls. Therefore, these studies indicate that no initial dose adjustment is necessary when administering enzalutamide to patients with hepatic impairment.