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Effect of Moderate Hepatic Impairment on the Pharmacokinetics of Vadadustat, an Oral Hypoxia‐Inducible Factor Prolyl Hydroxylase Inhibitor
Author(s) -
Chavan Ajit,
Burke Leontia,
Sawant Rishikesh,
NavarroGonzales Pamela,
Vargo Dennis,
Paulson Susan K.
Publication year - 2021
Publication title -
clinical pharmacology in drug development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.711
H-Index - 22
eISSN - 2160-7648
pISSN - 2160-763X
DOI - 10.1002/cpdd.927
Subject(s) - medicine , cmax , pharmacokinetics , dosing , tolerability , gastroenterology , adverse effect , renal function , confidence interval , area under the curve
Vadadustat is a hypoxia‐inducible factor prolyl hydroxylase inhibitor in development for the treatment of anemia of chronic kidney disease. This phase 1, open‐label, parallel‐group, single‐dose study evaluated the pharmacokinetics of 450‐mg vadadustat in adults with moderate hepatic impairment (Child‐Pugh class B) vs those with normal hepatic function. Primary end points were area under the plasma concentration–time curve (AUC) from dosing to last concentration and to infinity, as well as maximum concentration (C max ); additional pharmacokinetic parameters included time to C max (T max ) and half‐life. Safety and tolerability were also assessed. All enrolled participants (n = 16) completed the study. Demographics were similar in both groups (overall, 100% White; 62.5% female; mean age, 59.2 years). Vadadustat plasma exposure was higher in the moderate hepatic impairment group, whereas maximum concentration was similar between groups. Point estimates of the hepatic impairment : normal geometric mean ratios (90% confidence interval) for AUC from dosing to last concentration, AUC from dosing to infinity, and C max were 1.05 (0.82‐1.35), 1.06 (0.82‐1.36), and 1.02 (0.79‐1.32), respectively. Mean elimination half‐life was 5.8 and 7.8 hours in the normal and hepatic impairment groups, respectively. Treatment‐emergent adverse events were mostly mild in severity, and vadadustat was generally well tolerated. In conclusion, moderate hepatic impairment did not significantly impact vadadustat systemic exposure, and mild hepatic impairment is unlikely to alter vadadustat exposure.