Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor Roxadustat (FG-4592) for Treatment of Anemia in Chronic Kidney Disease: A Placebo-Controlled Study of Pharmacokinetic and Pharmacodynamic Profiles in Hemodialysis Patients

Abstract

Roxadustat (FG-4592), an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis, was evaluated in a phase 1b study in patients with end-stage renal disease with anemia on hemodialysis. Seventeen patients, on epoetin-alfa maintenance therapy with stable hemoglobin levels ≥10 g/dL, had epoetin-alfa discontinued on day 3 and were enrolled in this double-blind placebo-controlled study. Two cohorts were randomized 3:1 (roxadustat: placebo). Patients received single doses of roxadustat (1 or 2 mg/kg) or placebo 1 hour after hemodialysis on day 1 and 2 hours before dialysis on day 8. Maximum plasma concentration and area under the plasma concentration-time curve for patients receiving roxadustat were slightly more than dose proportional and elimination half-life ranged from 14.7 to 19.4 hours. Roxadustat was highly protein bound (99%) in plasma, and dialysis contributed a small fraction of the total clearance: only 4.56% and 3.04% of roxadustat recovered from the 1 and 2 mg/kg dose groups, respectively. Roxadustat induced transient elevations of endogenous erythropoietin that peaked between 7 and 14 hours after dosing and returned to baseline by 48 hours after dosing. Peak median endogenous erythropoietin levels were 96 mIU/mL and 268 mIU/mL for the 1- and 2-mg/kg doses, respectively, within physiologic range of endogenous erythropoietin responses to hypoxia at high altitude or after blood loss. No serious adverse events were reported, and there were no treatment- or dose-related trends in adverse event incidence.

Keywords: anemia; dialysis; erythropoietin; pharmacokinetics; roxadustat.

Figure 1

Study design.

Figure 2

A, Mean plasma concentration‐time profiles of roxadustat administered before and after HD by dosing group (N = 6 per dose group). B, Plasma erythropoietin levels after the first dose of 1.0 mg/kg (dashed green line) or 2.0 mg/kg (solid green line) roxadustat compared to historical epoetin‐alfa (red line) after intravenous dosing³⁴ (pharmacokinetic profile of intravenous epoetin‐alfa [100 IU/kg] administered to 10 patients with ESRD who were stable on continuous ambulatory peritoneal dialysis and not treated with epoetin‐alfa in the 2 months prior to the study). HD, hemodialysis; rhEPO, recombinant human erythropoietin.