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

• Published in: Clinical pharmacology in drug development Vol. 13; no. 1; pp. 111 - 116
• Main Authors: Pai, Sudhakar M., Yamada, Hiroyuki
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.01.2024
• Subjects: Bioavailability; CKD; clinical pharmacology; DDI; enarodustat; ESRD; HIF‐PH; JTZ‐951; pharmacokinetics; sevelamer carbonate; ESRD; HIF-PH; sevelamer carbonate; JTZ-951; enarodustat; DDI; pharmacokinetics; clinical pharmacology; CKD
• ISSN: 2160-763X; 2160-7648; 2160-7648
• DOI: 10.1002/cpdd.1336

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 (2400 mg) on the bioavailability of enarodustat (25 mg) when the 2 drugs were administered together (Treatment B) or when enarodustat was administered 3 hours after (Treatment C) or 1 hour 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 25 mg, with or without sevelamer carbonate, were safe and well tolerated in this study.