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

Abstract

The 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, 50mg), 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 (2-15mg), 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 (15mg, 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.