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

Dorien Groenendaal-van de Meent, Virginie Kerbusch, Rudiger Kaspera, Begona Barroso-Fernandez, Piergiorgio Galletti, Gernot K Klein, Martin den Adel, Dorien Groenendaal-van de Meent, Virginie Kerbusch, Rudiger Kaspera, Begona Barroso-Fernandez, Piergiorgio Galletti, Gernot K Klein, Martin den Adel

Abstract

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 (AUCinf), maximum concentration (Cmax), and terminal elimination half-life (t1/2) were assessed for roxadustat; AUC and Cmax 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 AUCinf was 223% and 195% in subjects with severely impaired kidney function and ESRD on HD/HDF, respectively, relative to subjects with normal kidney function; Cmax and t1/2 were comparable. The pharmacokinetic profile of roxadustat was not affected by HD/HDF. AUCinf and t1/2 for the metabolites of roxadustat increased in subjects with kidney impairment. The AUC and Cmax 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 Cmax and t1/2 of roxadustat were comparable among groups. Roxadustat and its metabolites were not cleared by HD/HDF. Clinical Trials Registration Number: NCT02965040.

Conflict of interest statement

V. Kerbusch reported personal fees from Astellas Pharma, Inc. during the conduct of the study and outside the submitted work. B. Barroso-Fernandez, M. den Adel, and R. Kaspera were employees of Astellas Pharma, Inc. during the conduct of the study. P. Galletti was contracted by Astellas Pharma, Inc. during the conduct of the study. D. Groenendaal-van de Meent is an employee of Astellas Pharma, Inc. G. Klein has nothing to disclose.

Figures

Fig. 1
Fig. 1
Study design and schedule of assessments for subjects with normal kidney function, severely impaired kidney function, or subjects with ESRD on CAPD or APD (a) and subjects with ESRD on HD/HDF (b). aSubjects received dialysis treatment. APD automated peritoneal dialysis, CAPD continuous ambulatory peritoneal dialysis, D day, ESRD end-stage renal disease, ESV end-of-study visit, HD hemodialysis, HDF hemodiafiltration
Fig. 2
Fig. 2
Mean (SD) plasma concentration–time profiles of roxadustat by renal function group (pharmacokinetic analysis set). ESRD end-stage renal disease, HD hemodialysis, HDF hemodiafiltration, SD standard deviation. During P1, subjects received a single roxadustat (100 mg) administration 2 h after completion of a dialysis session on day 1; during P2, subjects received a single roxadustat (100 mg) administration 2 h prior to the start of a dialysis session on day 1
Fig. 3
Fig. 3
Mean (SD) plasma concentration–time profiles of O-glucuronide-roxadustat (a), O-glucoside-roxadustat (b), and sulphate of hydroxy-roxadustat (c) (pharmacokinetic analysis set). ESRD end-stage renal disease, HD hemodialysis, HDF hemodiafiltration; SD standard deviation. During treatment period 1, subjects received a single roxadustat (100 mg) administration 2 h after completion of a dialysis session on day 1; during treatment period 2, subjects received a single roxadustat (100 mg) administration 2 h prior to the start of a dialysis session on day 1

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