Hemodialysis Clearance of Enarodustat (JTZ-951), an Oral Erythropoiesis Stimulating Agent, in Patients with End-Stage Renal Disease.

The dialysis clearance of enarodustat (JTZ-951) was determined in patients (N = 6) with end-stage renal disease on hemodialysis. Enarodustat (5 mg PO) was administered before (day 1) and after hemodialysis (day 8) with pharmacokinetic assessments on the 2 occasions. Dialysis clearance was based on plasma and dialysate enarodustat concentrations. Fraction of administered dose recovered in dialysate, total predialyzer and postdialyzer plasma enarodustat concentrations, and total and unbound venous plasma concentrations were determined. Hemodialysis did not significantly affect overall total concentrations with similar mean area under the plasma concentration-time curve from time 0 to infinity (coefficient of variation) of 3350 (26.4%) and 3640 (20.9%) ng · h/mL on days 1 and 8, respectively, and mean terminal half-life was 9.35 (11.9%) and 9.96 (18.7%) hours on the 2 occasions. Mean maximum concentration was somewhat lower on day 1 compared to day 8 (404 vs 559 ng/mL); the difference did not significantly affect total exposure (area under the plasma concentration-time curve from time 0 to infinity). Plasma protein binding was high (>99%) with similar binding on the 2 occasions, and total pre- and postdialyzer enarodustat concentrations were similar. Plasma unbound enarodustat concentrations decreased during dialysis, with a postdialysis rebound presumably due to re-equilibration with peripheral tissues. Mean unbound area under the plasma concentration-time curve from time 0 to infinity was marginally lower (∼22%) on day 1 compared to day 8. Dialysis clearance (0.415 L/h) was insignificant relative to dialyzer plasma flow (∼20 L/h), and the fraction of administered dose recovered in dialysate was small (6.74% of dose) with low intersubject variability (coefficient of variation, 14.7%). Thus, enarodustat can be administered regardless of dialysis schedule, and dose supplementation is not required in patients with end-stage renal disease on hemodialysis.