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

• Published in: Journal of clinical pharmacy and therapeutics Vol. 43; no. 5; pp. 633 - 639
• Main Authors: Shibata, T., Nomura, Y., Takada, A., Aoki, S., Katashima, M., Murakami, H.
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.10.2018
• Subjects: Administration, Oral; Adult; Anemia - drug therapy; Anemia - etiology; Area Under Curve; Cross-Over Studies; drug‐drug interaction; EKG; Geriatrics; Glycine - analogs & derivatives; Glycine - pharmacokinetics; Glycine - therapeutic use; Humans; Hyperphosphatemia; Hypoxia; Isoquinolines - pharmacokinetics; Isoquinolines - therapeutic use; Kidney diseases; Kidneys; Lanthanum; Lanthanum - adverse effects; lanthanum carbonate hydrate; Male; Pharmacokinetics; Prolyl hydroxylase; Renal Insufficiency, Chronic - complications; roxadustat; Young Adult; pharmacokinetics; lanthanum carbonate hydrate; drug-drug interaction; roxadustat
• ISSN: 0269-4727; 1365-2710; 1365-2710
• DOI: 10.1111/jcpt.12729

Summary What 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 (AUCinf), and maximum concentration (Cmax); the geometric least squares mean ratio (GMR; roxadustat + lanthanum carbonate/roxadustat alone) and corresponding 90% confidence interval (CI) was calculated for AUCinf and Cmax. 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 AUCinf and Cmax 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. What is new and conclusions Concomitant administration of a single oral dose of 100 mg roxadustat and 750 mg lanthanum carbonate three times daily did not impact the AUCinf or Cmax of roxadustat and was considered safe and well tolerated in non‐elderly healthy adult male Japanese subjects. Roxadustat is currently being investigated for the treatment of anaemia in chronic kidney disease. This study investigated the effect of lanthanum carbonate, a phosphate binder, on the pharmacokinetics, safety, and tolerability of a single oral dose of roxadustat in healthy nonelderly adult male subjects. Concomitant administration of roxadustat and lanthanum carbonate did not impact the AUCinf or Cmax of roxadustat.