Evaluation of the effect of lanthanum carbonate hydrate on the pharmacokinetics of roxadustat in non‐elderly healthy adult male subjects

Abstract

SummaryWhat is known and objective: Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor currently being investigated for the treatment of anemia in chronic kidney disease. Lanthanum carbonate is a phosphate binder that is commonly used to treat hyperphosphatemia in patients with chronic kidney disease. This study investigated the effect of lanthanum carbonate on the pharmacokinetics, safety and tolerability of a single oral dose of roxadustat in healthy non-elderly adult male subjects. Methods:This was an open-label, randomized, two-period, two-sequence crossover study in non-elderly healthy adult males. Subjects randomized to Group 1 received roxadustat alone during Period 1 and roxadustat concomitantly with lanthanum carbonate during Period 2; subjects randomized to Group 2 received roxadustat concomitantly with lanthanum carbonate during Period 1 and roxadustat alone during Period 2. All subjects received a single oral dose of 100 mg roxadustat on Day 1 in both periods. Subjects receiving concomitant lanthanum carbonate received 750 mg lanthanum carbonate three times daily on Days 1 and 2. Pharmacokinetic assessments were conducted on Days 1-4 in both periods. The primary study outcomes were the area under the concentration-time curve from the time of dosing extrapolated to infinity (AUC inf ), and maximum concentration (C max ); the geometric least squares mean ratio (GMR; roxadustat + lanthanum carbonate/roxadustat alone) and corresponding 90% confidence interval (CI) was calculated for AUC inf and C max .Safety was assessed by the occurrence of treatment-emergent adverse events (TEAEs), laboratory test results, vital signs and standard 12-lead electrocardiogram.Results and discussion: A total of 18 subjects were enrolled (Group 1, n = 9; Group 2, n = 9); no subjects discontinued from the study. Roxadustat was rapidly absorbed, reaching maximum plasma concentration between 1 and 4 hours. The GMRs for AUC inf and C max were 88.00% (90% CI: 84.01, 92.17) and 98.58% (90% CI: 92.92, 104.58), respectively. The 90% CIs for both parameters were within the no-effect boundaries of 80% and 125%, indicating a lack of effect of lanthanum carbonate on roxadustat absorption. No deaths or serious TEAEs occurred.

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

“…The AUC 0-∞ of roxadustat was 12% lower when roxadustat was administered concomitantly with lanthanum carbonate compared with roxadustat administered alone, whereas the mean C max , median t max , and mean t ½ were comparable when roxadustat was administered alone or concomitantly with lanthanum carbonate. 14 The current study indicated that calcium acetate significantly reduces roxadustat's exposure when coadministered with roxadustat, likely because of chelation with calcium ions. However, a study evaluating the effect of food on the pharmacokinetic properties of roxadustat found that administration of a single dose of 100 mg roxadustat given concomitantly with a meal that contained 184 mg of calcium did not result in a significant change in the AUC of roxadustat compared with its administration under fasted conditions.…”

Hypoxia-inducible factor–prolyl hydroxylase inhibitors in the treatment of anemia of chronic kidney disease

“…[69][70][71][72][73]75,76 Roxadustat and daprodustat are primarily oxidized by cytochrome P450 (CYP) 2C8, with a c l i n i c a l i n v e s t i g a t i o n VH Haase: HIF-PH inhibitors for anemia of CKD minor contribution of CYP3A4 to daprodustat metabolism. 81,82 In addition to CYP2C8-mediated oxidation, roxadustat undergoes phase 2 hydrophilic modification by glucuronidation and glucosidation. 75,83 Enarodustat is also metabolized by CYP enzymes, 72 whereas molidustat and vadadustat are primarily metabolized by uridine 5 0 -diphospho-glucuronosyltransferases.…”

Clinical Pharmacokinetics and Pharmacodynamics of Roxadustat

“…The pharmacokinetics of roxadustat after oral administration are well characterized (Table 1 ) and appear to be linear (Yu [ 71 ], Groenendaal [ 26 , 27 ], Groenendaal [ 28 ], Shibata [ 62 ], Shibata [ 63 ], Provenzano [ 55 ], Rekic [ 59 ], Groenendaal [ 29 , 30 ], Takada [ 67 ]). Roxadustat is readily absorbed after oral administration, has a moderate apparent volume of distribution, and is eliminated largely by metabolism (cytochrome P450 (CYP) 2C8, UDP-glucuronosyltransferase (UGT) 1A9).…”

“…Omeprazole had no clinically relevant effect on roxadustat pharmacokinetics [ 28 ]. Furthermore, lanthan and spherical carbon adsorbent had no clinically relevant effect on roxadustat pharmacokinetics [ 62 , 63 ]. Roxadustat did not influence warfarin [ 27 ].…”