Pharmacokinetics of Enarodustat in Non‐Japanese and Japanese Healthy Subjects and in Patients With End‐Stage Renal Disease on Hemodialysis

Abstract

AbstractThe pharmacokinetics of enarodustat were elucidated in healthy subjects and in patients with end‐stage renal disease (ESRD) on hemodialysis in phase 1 studies conducted in the United States and Japan. In healthy non‐Japanese and Japanese subjects, following single oral administration up to 400 mg, enarodustat was rapidly absorbed. Maximum plasma concentration and area under the plasma concentration‐time curve from the time of dosing to infinity were dose‐dependent, renal excretion of unchanged enarodustat was substantial (on average ≈45% of dose), and mean t1/2 of <10 hours indicated negligible accumulation with once‐daily dosing. In general, with daily dosing (25, 50 mg), accumulation at steady‐state was ≈1.5‐fold (t1/2(eff) ≈15 hours), presumably due to a decrease in renal drug excretion which is not clinically relevant in patients with ESRD. In the single‐ and multiple‐dose studies, plasma clearance (CL/F) was lower in healthy Japanese subjects. In non‐Japanese patients with ESRD on hemodialysis, following once‐daily dosing (2–15 mg), enarodustat was rapidly absorbed, steady‐state maximum plasma concentration and area under the plasma concentration‐time curve during the dosing interval were dose‐dependent, and interindividual variability in the exposure parameters was low‐to‐moderate (coefficient of variation, 27%–39%). Steady‐state CL/F was similar across doses, renal drug excretion was not significant (<10% of dose), mean t1/2 and t1/2(eff) were similar (overall, 8.97–11.6 hours), and accumulation was minimal (≈20%), demonstrating predictable pharmacokinetics. Japanese patients with ESRD on hemodialysis (15 mg, single dose) exhibited similar pharmacokinetics with mean t1/2 of 11.3 hours and low interindividual variability in the exposure parameters, albeit with lower CL/F versus non‐Japanese patients. Body weight‐adjusted clearance values were generally similar in non‐Japanese and Japanese healthy subjects and also in patients with ESRD on hemodialysis.