Effect of Moderate Hepatic Impairment on the Pharmacokinetics and Pharmacodynamics of Roxadustat, an Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor
| Autor: | Dorien Groenendaal-van de Meent, Martin den Adel, Jan Noukens, Marloes Schaddelee, A. Alexiev, Sanne Rijnders, Axel Krebs-Brown, L. Mateva |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Adult
Liver Cirrhosis Male medicine.medical_specialty Hypoxia-Inducible Factor 1 Adolescent 030232 urology & nephrology Glycine 030204 cardiovascular system & hematology Pharmacology 03 medical and health sciences Young Adult 0302 clinical medicine Pharmacotherapy Pharmacokinetics Internal medicine medicine Humans Pharmacology (medical) Original Research Article Erythropoietin Aged Aged 80 and over business.industry Liver Diseases Prolyl-Hydroxylase Inhibitors General Medicine Middle Aged medicine.disease Isoquinolines Endocrinology Tolerability Hypoxia-inducible factors Pharmacodynamics Area Under Curve Female business medicine.drug Kidney disease Half-Life |
| Zdroj: | Clinical Drug Investigation |
| ISSN: | 1179-1918 1173-2563 |
| Popis: | Background and Objective Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor in phase III development for the treatment of anaemia associated with chronic kidney disease. This study evaluated the effects of moderate hepatic impairment on roxadustat pharmacokinetics, pharmacodynamics and tolerability. Methods This was an open-label study in which eight subjects with moderate hepatic impairment (liver cirrhosis Child–Pugh score 7–9) and eight subjects with normal hepatic function (matched for body mass index, age and sex) received a single oral 100 mg roxadustat dose under fasted conditions. Blood samples were collected until 144 h post-dose in subjects with moderate hepatic impairment and until 96 h post-dose in subjects with normal hepatic function. Results In subjects with moderate hepatic impairment, area under the concentration–time curve (AUC) from the time of drug administration to infinity (AUC∞) and observed maximum concentration (Cmax) were 23 % higher [geometric least-squares mean ratio (GMR) 123 %; 90 % CI 86.1–175] and 16 % lower (GMR 83.6 %; 90 % CI 67.5–104), respectively, than in subjects with normal hepatic function. Mean terminal half-life (t½) appeared to be longer (17.7 vs. 12.8 h) in subjects with moderate hepatic impairment, however intersubject variability on apparent total systemic clearance after single oral dosing (CL/F), apparent volume of distribution at equilibrium after oral administration (Vz/F) and t½ was approximately twofold higher. Erythropoietin (EPO) baseline-corrected AUC from administration to the last measurable EPO concentration (AUCE,last) and maximum effect (Emax) were 31 % (GMR 68.95 %; 90 % CI 29.29–162.29) and 48 % (GMR 52.29 %; 90 % CI 28.95–94.46) lower, respectively, than in subjects with normal hepatic function. The single oral roxadustat dose was generally well tolerated. Conclusions This study demonstrated the effect of moderate hepatic impairment on the pharmacokinetics and pharmacodynamics of roxadustat relative to subjects with normal hepatic function. These differences are not expected to be of clinical significance. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink