title: Effect of Moderate Hepatic Impairment on the Pharmacokinetics and Pharmacodynamics of Roxadustat, an Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor.
abstract: 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 (C max) 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 (t ½) 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 (V z/F) and t ½ was approximately twofold higher. Erythropoietin (EPO) baseline-corrected AUC from administration to the last measurable EPO concentration (AUCE,last) and maximum effect (E max) 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.
authors.affiliation: Astellas Pharma Europe B.V., Leiden, The Netherlands.
authors.forename: Dorien
authors.initials: D
authors.lastname: Groenendaal-van de Meent
authors.affiliation: Astellas Pharma Europe B.V., Leiden, The Netherlands.
authors.forename: Martin den
authors.initials: MD
authors.lastname: Adel
authors.affiliation: Kinesis Pharma B.V., Breda, The Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Noukens
authors.affiliation: Astellas Pharma Europe B.V., Leiden, The Netherlands.
authors.forename: Sanne
authors.initials: S
authors.lastname: Rijnders
authors.affiliation: Astellas Pharma Europe B.V., Leiden, The Netherlands.
authors.forename: Axel
authors.initials: A
authors.lastname: Krebs-Brown
authors.affiliation: Gastroenterology Clinic, University Hospital St Ivan Rilski, Medical University-Sofia, COMAC Medical Ltd, Sofia, Bulgaria.
authors.forename: Lyudmila
authors.initials: L
authors.lastname: Mateva
authors.affiliation: Gastroenterology Clinic, University Hospital St Ivan Rilski, Medical University-Sofia, COMAC Medical Ltd, Sofia, Bulgaria.
authors.forename: Assen
authors.initials: A
authors.lastname: Alexiev
authors.affiliation: Astellas Pharma Europe B.V., Leiden, The Netherlands. marloes.schaddelee@astellas.com.|Business Development, Transaction Execution Group, Astellas Pharma Inc., Sylviusweg 62, PO Box 344, 2300 AH, Leiden, The Netherlands. marloes.schaddelee@astellas.com.
authors.forename: Marloes
authors.initials: M
authors.lastname: Schaddelee
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D004921:Erythropoietin / Q000378:metabolism; D005260:Female; D005998:Glycine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors*; D007546:Isoquinolines / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D008103:Liver Cirrhosis / Q000378:metabolism; D008107:Liver Diseases / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D064800:Prolyl-Hydroxylase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D051793:Hypoxia-Inducible Factor 1; D007546:Isoquinolines; D064800:Prolyl-Hydroxylase Inhibitors; D004921:Erythropoietin; D005998:Glycine; C584543:roxadustat