Dorien Groenendaal-van de Meent1, Virginie Kerbusch2, Begona Barroso-Fernandez3, Martin den Adel4, Jan van Dijk4, Georg Golor5, Marloes Schaddelee4. 1. Department of Clinical Pharmacology and Exploratory Development, Astellas Pharma Europe B.V., Leiden, the Netherlands. Electronic address: dorien.groenendaal@astellas.com. 2. PharmAspire B.V., Wijchen, the Netherlands. 3. Department of Drug Discovery Research and Bioanalysis, Astellas Pharma Europe B.V., Leiden, the Netherlands. 4. Department of Clinical Pharmacology and Exploratory Development, Astellas Pharma Europe B.V., Leiden, the Netherlands. 5. Department of Clinical Operations, Parexel GmbH, Berlin, Germany.
Abstract
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 AUC0-∞ and Cmax. 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 AUC0-∞ by 67% (90% CI, 63.5%-69.3%) and 46% (90% CI, 41.7%-50.9%), respectively, and reduced roxadustat's Cmax 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 AUC0-∞ 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 Cmax 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.
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 AUC0-∞ and Cmax. 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 AUC0-∞ by 67% (90% CI, 63.5%-69.3%) and 46% (90% CI, 41.7%-50.9%), respectively, and reduced roxadustat's Cmax 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 AUC0-∞ 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 Cmax 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.
Authors: Dorien Groenendaal-van de Meent; Martin den Adel; Virginie Kerbusch; Jan van Dijk; Tomohisa Shibata; Kota Kato; Marloes Schaddelee Journal: Clin Pharmacol Drug Dev Date: 2022-02-19