Effect of Moderate Hepatic Impairment on the Pharmacokinetics and Pharmacodynamics of Roxadustat, an Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor

Abstract

Background and ObjectiveRoxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor in phase III development for the treatment of anaemia associated with chronic kidney disease. This study evaluated the effects of moderate hepatic impairment on roxadustat pharmacokinetics, pharmacodynamics and tolerability.MethodsThis was an open-label study in which eight subjects with moderate hepatic impairment (liver cirrhosis Child–Pugh score 7–9) and eight subjects with normal hepatic function (matched for body mass index, age and sex) received a single oral 100 mg roxadustat dose under fasted conditions. Blood samples were collected until 144 h post-dose in subjects with moderate hepatic impairment and until 96 h post-dose in subjects with normal hepatic function.ResultsIn subjects with moderate hepatic impairment, area under the concentration–time curve (AUC) from the time of drug administration to infinity (AUC∞) and observed maximum concentration (Cmax) were 23 % higher [geometric least-squares mean ratio (GMR) 123 %; 90 % CI 86.1–175] and 16 % lower (GMR 83.6 %; 90 % CI 67.5–104), respectively, than in subjects with normal hepatic function. Mean terminal half-life (t½) appeared to be longer (17.7 vs. 12.8 h) in subjects with moderate hepatic impairment, however intersubject variability on apparent total systemic clearance after single oral dosing (CL/F), apparent volume of distribution at equilibrium after oral administration (Vz/F) and t½ was approximately twofold higher. Erythropoietin (EPO) baseline-corrected AUC from administration to the last measurable EPO concentration (AUCE,last) and maximum effect (Emax) were 31 % (GMR 68.95 %; 90 % CI 29.29–162.29) and 48 % (GMR 52.29 %; 90 % CI 28.95–94.46) lower, respectively, than in subjects with normal hepatic function. The single oral roxadustat dose was generally well tolerated.ConclusionsThis study demonstrated the effect of moderate hepatic impairment on the pharmacokinetics and pharmacodynamics of roxadustat relative to subjects with normal hepatic function. These differences are not expected to be of clinical significance.

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

“…The duration of the washout period was selected to ensure full clearance of roxadustat. Including PK and safety assessments and the ≥3‐day washout, the total time between roxadustat doses was a minimum of 7 days, which is more than 10 times the t ½ (~12 hours) of roxadustat, as reported in a previous Phase 1 study …”

“…Including PK and safety assessments and the ≥3-day washout, the total time between roxadustat doses was a minimum of 7 days, which is more than 10 times the t ½ (~12 hours) of roxadustat, as reported in a previous Phase 1 study. 8 The primary objective of this study was to evaluate the effect of 750 mg lanthanum carbonate TID (2250 mg/day) on the PK of a single oral dose of 100 mg roxadustat in non-elderly healthy adult male subjects. The secondary objective was to evaluate the safety of a single oral dose of 100 mg roxadustat administered concomitantly with lanthanum carbonate (750 mg, TID) in non-elderly healthy adult male Japanese subjects.…”

“…In addition, roxadustat has been shown to improve iron availability by reducing hepcidin, and may reduce the need for intravenous iron . Roxadustat reaches maximum plasma concentration within 2 hours of oral administration and is eliminated by phase I oxidation (cytochrome P450 2C8) and phase II conjugation (glucuronidation via uridine diphosphate‐glucuronosyltransferase and glucosidation); the terminal elimination half‐life (t ½ ) is approximately 12 hours in healthy subjects . The solubility of roxadustat is pH dependent and absorption has been shown to be unaffected by food (data on file).…”

“…[4][5][6][7] Roxadustat reaches maximum plasma concentration within 2 hours of oral administration and is eliminated by phase I oxidation (cytochrome P450 2C8) and phase II conjugation (glucuronidation via uridine diphosphate-glucuronosyltransferase and glucosidation); the terminal elimination half-life (t ½ ) is approximately 12 hours in healthy subjects. 8 The solubility of roxadustat is pH dependent and absorption has been shown to be unaffected by food (data on file). Roxadustat is currently in Phase 3 trials for the treatment of anemia in patients with CKD, and has demonstrated safety and efficacy in Phase 2 studies in patients with CKD on dialysis 4,6,7 and not on dialysis.…”

Evaluation of Food and Spherical Carbon Adsorbent Effects on the Pharmacokinetics of Roxadustat in Healthy Nonelderly Adult Male Japanese Subjects

“…Roxadustat is rapidly absorbed after oral administration, reaches maximum plasma concentration within 2 hours, and is highly bound to albumin; the terminal elimination half-life (t ½ ) is approximately 12 hours in healthy subjects after a single dose. 11 The primary elimination pathways are phase I oxidation (cytochrome P450 2C8) and phase II conjugation (glucuronidation via uridine diphosphateglucuronosyltransferase and glucosidation). The solubility of roxadustat is pH dependent and ranges from 0.001 mg/mL in a simulated gastric fluid (pH 1.2) to 3.7 mg/mL in a potassium phosphate buffer (pH 7.5).…”