Abstract
Background and Aims
Roxadustat is an orally active hypoxia-inducible factor prolyl hydroxylase inhibitor used at titrated doses to treat anaemia in CKD patients. This study investigated the pharmacokinetics (PK), metabolic profile, pharmacodynamics, and safety of roxadustat in subjects with different degrees of renal function (RF).
Method
This was a phase 1, open-label study conducted in Germany and the United Kingdom (EudraCT Number: 2015-002565-28). Subjects were enrolled in four RF groups: normal RF (eGFR ≥90 mL/min/1.73 m2); severely impaired RF (not on dialysis; eGFR <30 mL/min/1.73 m2); end-stage renal disease (ESRD) on continuous ambulatory or automated peritoneal dialysis (CAPD/APD); or ESRD on 4-hour haemodialysis or haemodiafiltration (HD/HDF). Subjects in the normal RF, severely impaired RF, and ESRD on CAPD/APD groups received a single dose of 100-mg oral roxadustat on Day 1. A single-sequence design with two treatment periods (P1/P2) separated by a washout period was used for subjects with ESRD on HD/HDF; a single administration of 100-mg oral roxadustat occurred 2 hours after completion of a HD/HDF session (P1) and 2 hours before initiation of a HD/HDF session, 2 days after the previous session (P2). Plasma and urine PK of roxadustat and its circulating metabolites (O-glucuronide-, O-glucoside-, and sulphate of hydroxy-roxadustat) and plasma erythropoietin (EPO) were evaluated. Continuous heart rate monitoring was conducted.
Results
Of 73 screened subjects, 34 (46.6%) were enrolled and received roxadustat (normal RF, n=12; severely impaired RF, n=9; ESRD on CAPD, n=1; ESRD on HD/HDF, n=12). The geometric least-square mean ratio of area under the plasma concentration-time curve (AUC) from administration to infinity (AUCinf) relative to subjects with normal RF was 223% (90% CI: 185, 268) and 195% (90% CI: 165, 229) in subjects with severely impaired RF and in those with ESRD on HD/HDF, respectively. Roxadustat’s maximum concentration (Cmax) and terminal elimination half-life (t1/2) were comparable between groups. The PK of roxadustat and its metabolites were not affected by HD/HDF. In subjects with normal RF, the amount of roxadustat excreted unchanged in urine was <1%; urinary excretion and renal clearance of roxadustat and its metabolites decreased with lower baseline RF. Mean AUCinf and t1/2 for roxadustat’s circulating metabolites were higher in subjects with severely impaired RF and with ESRD on HD/HDF than in those with normal RF. Metabolite to parent ratio of AUCinf was <1% for O-glucuronide- and O-glucoside-roxadustat and <10% for sulphate of hydroxy-roxadustat. EPO baseline-corrected AUC from administration to last measurable concentration and EPO maximum effect were higher in subjects with severely impaired RF or with ESRD on HD/HDF than in those with normal RF.
Conclusion
The AUC for roxadustat and its metabolites was higher in patients with severely impaired RF or with ESRD on HD/HDF than in those with normal RF. Roxadustat’s Cmax and t1/2 were comparable among all groups. Roxadustat and its metabolites were not significantly cleared by HD/HDF.
In Vitro and Clinical Pharmacokinetic Studies of the Effects of Iron-Containing Agents on Vadadustat, an Oral Hypoxia-Inducible Factor–Prolyl Hydroxylase Inhibitor
