Effect of the Phosphate Binder Sevelamer Carbonate on the Bioavailability of Enarodustat, an Oral Erythropoiesis Stimulating Agent.

Abstract

Enarodustat is an orally available hypoxia-inducible factor-prolyl hydroxylase inhibitor which can correct the erythropoietic capacity and improve anemia in chronic kidney disease. Sevelamer carbonate, a non-calcium-based polymeric resin, is one of the commonly prescribed agents for the management of hyperphosphatemia in patients undergoing hemodialysis. This was an open-label, crossover study in healthy male subjects (N=12) that evaluated the effect of sevelamer carbonate (2400mg) on the bioavailability of enarodustat (25mg) when the 2 drugs were administered together (Treatment B) or when enarodustat was administered 3hours after (Treatment C) or 1hour before (Treatment D) sevelamer carbonate compared to enarodustat alone (Treatment A). With coadministration of the 2 drugs (Treatment B), enarodustat Cmax and AUCinf reductions were 53% and 45%, respectively. For Treatment C, Cmax and AUCinf reductions were 11% and 6%, respectively, and for Treatment D the corresponding values were 8% and 20%. Thus, coadministration of enarodustat and sevelamer carbonate resulted in a substantial reduction (≈50%) in the oral bioavailability of enarodustat. However, the interaction was substantially mitigated by staggering the administration of enarodustat and sevelamer carbonate. Administration of 4 single oral doses of enarodustat 25mg, with or without sevelamer carbonate, were safe and well tolerated in this study.