Effect of Kidney Function and Dialysis on the Pharmacokinetics and Pharmacodynamics of Roxadustat, an Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor

BACKGROUND AND OBJECTIVES: Roxadustat is an orally active hypoxia-inducible factor prolyl hydroxylase inhibitor for anemia in chronic kidney disease. The pharmacokinetics, metabolic profile, and pharmacodynamics of roxadustat were investigated in subjects with different degrees of kidney function. METHODS: This phase 1 open-label study enrolled subjects with normal and severely impaired kidney function, and end-stage renal disease (ESRD) on continuous ambulatory peritoneal dialysis (CAPD) or automated peritoneal dialysis (APD) or hemodialysis/hemodiafiltration (HD/HDF). All subjects received a single 100-mg dose of oral roxadustat. Within a single-sequence, two-treatment period design (P1/P2), subjects with ESRD on HD/HDF received roxadustat 2 h after (P1) and 2 h before (P2) a dialysis session. Area under the plasma concentration–time curve (AUC) from administration to infinity (AUC(inf)), maximum concentration (C(max)), and terminal elimination half-life (t(1/2)) were assessed for roxadustat; AUC and C(max) were assessed for erythropoietin. RESULTS: Thirty-four subjects were enrolled and received roxadustat (normal kidney function, n = 12; severely impaired kidney function, n = 9; ESRD on CAPD/APD, n = 1; ESRD on HD/HDF, n = 12). The geometric least-square mean ratio of AUC(inf) was 223% and 195% in subjects with severely impaired kidney function and ESRD on HD/HDF, respectively, relative to subjects with normal kidney function; C(max) and t(1/2) were comparable. The pharmacokinetic profile of roxadustat was not affected by HD/HDF. AUC(inf) and t(1/2) for the metabolites of roxadustat increased in subjects with kidney impairment. The AUC and C(max) of erythropoietin increased in subjects with severely impaired kidney function or ESRD on HD/HDF. Roxadustat was well tolerated. CONCLUSIONS: Kidney function impairment increased the AUC of roxadustat and its metabolites. The C(max) and t(1/2) of roxadustat were comparable among groups. Roxadustat and its metabolites were not cleared by HD/HDF. Clinical Trials Registration Number: NCT02965040. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13318-020-00658-w) contains supplementary material, which is available to authorized users.