Effect of Moderate Hepatic Impairment on the Pharmacokinetics of Vadadustat, an Oral Hypoxia‐Inducible Factor Prolyl Hydroxylase Inhibitor

Abstract

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 450mg 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.

Clinical Pharmacokinetics and Pharmacodynamics of Roxadustat

“…This usually requires a short administration interval. The other HIF stabilizer vadadustat, with a dosing interval of 24 h, has an even shorter t ½ of 5.8 h (Chavan [ 9 ]. Although the roxadustat t ½ is approximately 12 h, the suggested administration interval is 48–72 h for a 100 mg dose, indicating that the target effect on ∆Hb more constantly and continuously follows downstream to the intermittent rise and decrease in EPO levels.…”

Effect of Phosphate Binders and a Dietary Iron Supplement on the Pharmacokinetics of a Single Dose of Vadadustat in Healthy Adults

“…Additional samples were taken at 9 and 48 hours after dosing in study 1 and 8 hours after dosing in study 2. Plasma concentrations of vadadustat and its metabolite vadadustat‐O‐glucuronide were determined using validated liquid chromatography with tandem mass spectrometry; additional details have been published previously 19 and are also presented in Table S2 . The lower limit of quantification was 100 ng/mL for vadadustat in both study 1 and study 2 and was 100 and 5.0 ng/mL for vadadustat‐O‐glucuronide in study 1 and study 2, respectively; samples below the limit of quantification were reported as 0.…”

“…The terminal elimination half‐life (t ½ ) of vadadustat is 4.7 hours in healthy adults but ranges from 7.9 to 9.1 hours in patients with non–dialysis‐ and dialysis‐dependent CKD, respectively 18 . Among patients with mild or moderate hepatic impairment, single oral administration of vadadustat has been shown to be well tolerated, with no clinically meaningful effect on systemic exposure 19 …”

“…18 Among patients with mild or moderate hepatic impairment, single oral administration of vadadustat has been shown to be well tolerated, with no clinically meaningful effect on systemic exposure. 19 As hyperphosphatemia and anemia are common complications of CKD, phosphate binders and oral iron supplements are anticipated to be used concomitantly with vadadustat in a clinical setting, suggesting that there is a potential for drug-drug interactions (DDIs). In particular, by forming a chelation complex with these agents, vadadustat absorption from the gastrointestinal tract may be altered.…”

“… 18 Among patients with mild or moderate hepatic impairment, single oral administration of vadadustat has been shown to be well tolerated, with no clinically meaningful effect on systemic exposure. 19 …”