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

• Published in: European journal of drug metabolism and pharmacokinetics Vol. 46; no. 1; pp. 141 - 153
• Main Authors: Groenendaal-van de Meent, Dorien, Kerbusch, Virginie, Kaspera, Rudiger, Barroso-Fernandez, Begona, Galletti, Piergiorgio, Klein, Gernot K., den Adel, Martin
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.01.2021
• Subjects: Administration, Oral; Adult; Aged; Biomedical and Life Sciences; Biomedicine; Female; Glycine - administration & dosage; Glycine - analogs & derivatives; Glycine - pharmacokinetics; Human Physiology; Humans; Isoquinolines - administration & dosage; Isoquinolines - pharmacokinetics; Kidney - drug effects; Kidney - metabolism; Kidney Failure, Chronic - metabolism; Kidney Failure, Chronic - therapy; Male; Medical Biochemistry; Middle Aged; Original; Original Research Article; Pharmaceutical Sciences/Technology; Pharmacology/Toxicology; Pharmacy; Prolyl-Hydroxylase Inhibitors - administration & dosage; Prolyl-Hydroxylase Inhibitors - pharmacokinetics; Renal Dialysis - trends
• ISSN: 0378-7966; 2107-0180; 2107-0180
• DOI: 10.1007/s13318-020-00658-w

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.