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

Abstract

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.

Evaluation of Hemoglobin Response to Treatment With Enarodustat Using Pharmacometric Approach in Japanese Anemic Patients With Chronic Kidney Disease

“…The population estimates of CL/F from the final PK model (0.892 L/h) was in agreement with the value (0.820 L/h) calculated from noncompartmental analysis with intensive PK data in Japanese patients with HDD‐CKD 32 . The population estimates of V/F was 10.9 L. Enarodustat had high plasma protein binding (>99%) in patients with end‐stage renal disease 33 and was not substrate of the hepatic uptake transporters such as organic anion transporting polypeptides 1B1 (OATP1B1) and OATP1B3 in vitro. Considering these PK characteristics, the distribution volume of enarodustat was considered relatively small.…”

Treatment of anemia associated with chronic kidney disease with the HIF prolyl hydroxylase inhibitor enarodustat: A review of the evidence

“…30 Following the administration of 5 mg enarodustat to hemodialysis patients, more than 99% of enarodustat in plasma is mainly bound to albumin. 31 The percent distribution of enarodustat to human blood cells (in vitro) was 2.5%-6.8%. In vitro studies with hepatic microsomes and cytochrome P450 (CYP) isoenzymes showed that enarodustat was slightly metabolized, mainly by CYP2C8 and CYP2C9 with minor involvement of CYP3A4.…”

“…Therefore, enarodustat can be administered regardless of the dialysis schedule, and dose supplementation is not required for hemodialysis patients. 31…”

“…However, staggered administration (enarodustat administered 3 h after or 1 h before the administration of sevelamer carbonate) substantially reduced the effect of sevelamer carbonate on both the peak (C max ) and total (AUC inf ) level of enarodustat 30 . Following the administration of 5 mg enarodustat to hemodialysis patients, more than 99% of enarodustat in plasma is mainly bound to albumin 31 . The percent distribution of enarodustat to human blood cells (in vitro) was 2.5%–6.8%.…”

“…A study in US hemodialysis patients (NCT01978587) showed that the hemodialysis effect on the pharmacokinetics of enarodustat was minimal. Therefore, enarodustat can be administered regardless of the dialysis schedule, and dose supplementation is not required for hemodialysis patients 31 …”