Chemical formula: C₁₄H₁₁ClN₂O₄ Molecular mass: 306.041 g/mol PubChem compound: 23634441
Vadadustat is a hypoxia-inducible factor prolyl-hydroxylase inhibitor which leads to increased cellular levels of hypoxia-inducible factor thereby stimulating endogenous erythropoietin (EPO) production, increasing iron mobilization and red blood cell production, resulting in gradual rate of rise in Hb.
Vadadustat did not cause any clinically significant QTc prolongation following a 600 mg and 1200 mg dose in healthy subjects.
Vadadustat is rapidly absorbed after single and repeated oral doses. Median time to peak plasma concentrations (Tmax) is approximately 2 to 3 hours.
No significant accumulation has been observed after repeated dosing in healthy subjects.
Vadadustat may be administered with or without food. Administration of a 450 mg vadadustat tablet with a standard high-fat meal decreased Cmax by 27% and decreased the AUC by 6%, relative to fasted conditions.
Vadadustat is highly protein bound (greater than or equal to 99.5% in human plasma). The mean blood to plasma ratio was less than 1 (0.50 to 0.55) suggesting minimal sequestration into red blood cells (RBCs). In patients with CKD the apparent volume of distribution (Vd/F) was 11.6 L.
Vadadustat is primarily metabolised via direct glucuronidation by UDP-glucuronosyltransferase (UGT) enzymes to O-glucuronide conjugates. The major metabolite vadadustat-O-glucuronide (15% of the AUC of plasma radioactivity). Vadadustat acyl glucuronide (0.047% of the total radioactivity in plasma) is a minor metabolite. Vadadustat metabolites are not active.
The half-life of vadadustat in DD-CKD patients was 9.2 hours. After a single oral dose of radiolabelled vadadustat 650 mg to healthy adults, 85.9% of the dose was recovered (58.9% in urine and 26.9% in faeces). The excretion for vadadustat (unchanged form) was less than 1% in urine and about 9% in faeces.
Vadadustat exposures in DD-CKD patients were approximately 2-fold higher compared to healthy subjects. No significant differences in pharmacokinetics (Cmax, AUC or mean half-life) were observed when vadadustat was administered 4 hours before dialysis or 2 hours after dialysis.
Moderate hepatic impairment (Child-Pugh Class B) did not significantly affect the AUC or Cmax of vadadustat compared to healthy subjects. The half-life and apparent total body clearance for vadadustat were comparable between subjects with normal hepatic function and subjects with moderate hepatic function. Vadadustat has not been studied in severe hepatic impairment (Child-Pugh Class C).
Population pharmacokinetic analysis did not suggest any clinically significant effects of age (19 to 104 years), gender, race, or body weight (47 to 118 kg) on the pharmacokinetics of vadadustat.
A sensitivity analysis at body weight extremes (30.1 to 204 kg) showed that the dose titration algorithm resulted in predicted Hb levels at the limits of the predefined window of 10 to 12 g/dL. Therefore, no dose-adjustment is proposed at body weight extremes.
In non-clinical trials, mortalities were observed in mice, rats, rabbits and dogs due to exaggerated pharmacological effects such as polycythemia and hyperviscosity of the blood, leading to thrombosis and organ infarct at dose levels that were clinically relevant (starting from exposure multiples of 0.04 to the maximum recommended therapeutic dose of 600 mg).
Non-clinical data reveal no other special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity or carcinogenic potential.
Vadadustat was not teratogenic in either the rat or the rabbit up to the highest dose level tested (160 mg/kg/day and 50 mg/kg/day, respectively), corresponding to 1.7 and 0.16 times the human exposure at the 600 mg dose (based on AUC in NDD-CKD patients), respectively, in the dams. Development effects were noted only in the rat at dose levels corresponding to 1.7 times the human exposure at the 600 mg dose; characterised as a decrease in foetal body weight and an increased incidence of a reduction in skeletal ossification, both of which were considered secondary to the decline in body weight and food consumption in the pregnant dams. However, in a rat dose finding study, at doses that caused significant maternal toxicity, there was an increase in postimplantation loss at ≥120 mg/kg/day and decreased foetal body weight at 240 mg/kg/day, but no teratogenicity.
Vadadustat was excreted in the milk in rats with a ratio of milk to plasma of up to 14.49.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
