Effect of Kidney Function and Dialysis on the Pharmacokinetics and Pharmacodynamics of Roxadustat, an Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor
| Autor: | Rudiger Kaspera, Gernot K Klein, Begona Barroso-Fernandez, Virginie Kerbusch, Dorien Groenendaal-van de Meent, Martin den Adel, Piergiorgio Galletti |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Adult
Male medicine.medical_specialty medicine.medical_treatment Cmax Urology Glycine Renal function Administration Oral Kidney 030226 pharmacology & pharmacy 03 medical and health sciences 0302 clinical medicine Renal Dialysis medicine Humans Pharmacology (medical) Original Research Article Dialysis Aged Pharmacology business.industry Continuous ambulatory peritoneal dialysis Prolyl-Hydroxylase Inhibitors Middle Aged medicine.disease Isoquinolines Erythropoietin 030220 oncology & carcinogenesis Pharmacodynamics Kidney Failure Chronic Female Hemodialysis business Kidney disease medicine.drug |
| Zdroj: | European Journal of Drug Metabolism and Pharmacokinetics |
| ISSN: | 2107-0180 0378-7966 |
| Popis: | 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. Electronic supplementary material The online version of this article (10.1007/s13318-020-00658-w) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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