Effect of the Phosphate Binders Sevelamer Carbonate and Calcium Acetate on the Pharmacokinetics of Roxadustat After Concomitant or Time-separated Administration in Healthy Individuals

Purpose: Roxadustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, treats anemia in chronic kidney disease. Hyperphosphatemia, a common complication in chronic kidney disease, is treated with phosphate binders (PBs). This study in healthy individuals investigated the effect of 2 PBs, sevelamer carbonate and calcium acetate, on the pharmacokinetic properties of a single oral dose of roxadustat administered concomitantly or with a time lag.

Methods: This 2-part, Phase I study was conducted with an open-label, randomized, 3-way (part 1) or 5-way (part 2) crossover design, with 5-day treatment periods. On day 1 of each period, participants received 200 mg roxadustat administered alone or (1) concomitantly with sevelamer carbonate (2400 mg) or calcium acetate (1900 mg) (part 1) or (2) 1 hour before or 1, 2, or 3 hours after sevelamer carbonate (part 2A) or calcium acetate (part 2B); 5 additional PB doses were administered during 2 days. In both parts, PBs were administered with meals. Primary pharmacokinetic variables were AUC_0-∞ and C_max. FINDINGS: Twenty-four individuals were randomized in part 1; 60 individuals were randomized in part 2 (part 2A, n = 30; part 2B, n = 30). All participants completed the study in part 1; 28 and 27 individuals completed the study in part 2A and part 2B, respectively. Compared with roxadustat alone, concomitant sevelamer carbonate and calcium acetate administration reduced roxadustat's AUC_0-∞ by 67% (90% CI, 63.5%-69.3%) and 46% (90% CI, 41.7%-50.9%), respectively, and reduced roxadustat's C_max by 66% (90% CI, 61.6%-69.4%) and 52% (90% CI, 46.2%-57.2%), respectively. This effect was attenuated when roxadustat and PB administration occurred with a time lag. Roxadustat's AUC_0-∞ was reduced by 41% and 22% to 25%, respectively, when roxadustat was administered 1 hour before or 1 to 3 hours after sevelamer carbonate and by 31% and 14% to 18%, respectively, when administered 1 hour before or 1 to 3 hours after calcium acetate. Roxadustat's C_max was reduced by 26% and 12%, respectively, when roxadustat was administered 1 hour before and 1 hour after sevelamer carbonate; it was reduced by 19% when administered 1 hour before calcium acetate and was not affected when administered 1 hour after. Roxadustat was well tolerated.

Implications: Concomitant administration of roxadustat with sevelamer carbonate or calcium acetate reduced exposure to roxadustat in healthy individuals. This effect was attenuated when roxadustat was administered ≥1 hour before or after either PB. Results from this study helped inform dosing and administration guidelines aimed at reducing interactions between roxadustat and these PBs.