Indications
Vadadustat is prescribed for the treatment of symptomatic anemia associated with chronic kidney disease (CKD) in adults who are on chronic maintenance dialysis.
Pharmacodynamics
In clinical comparisons, vadadustat has been evaluated against darbepoetin alfa for treating anemia in adults with dialysis-dependent chronic kidney disease. Vadadustat demonstrated non-inferiority to darbepoetin alfa by successfully achieving the primary endpoint of hemoglobin levels. In healthy individuals administered doses ranging from 600 mg to 1200 mg, vadadustat showed no significant effect on QTc prolongation. Furthermore, patients treated with vadadustat displayed risk levels for death, myocardial infarction, and stroke similar to those treated with darbepoetin alfa. However, usage of vadadustat may lead to adverse events such as thromboembolic occurrences, hepatic impairment, hepatotoxicity, seizures, and elevated blood pressure.
Absorption
Vadadustat is quickly absorbed following both single and multiple dose administrations, with a Tmax ranging from 2 to 3 hours. In healthy subjects, repeated doses showed no significant accumulation. The pharmacokinetics of a 450 mg vadadustat tablet are influenced by food intake, with a standard high-fat meal reducing Cmax and AUC by 27% and 6%, respectively, though it can be taken with or without food. The mean blood-to-plasma ratio of vadadustat, which ranges from 0.50 to 0.55, indicates minimal sequestration into red blood cells.
Metabolism
Vadadustat undergoes primary metabolism through UDP-glucuronosyltransferase (UGT) enzymes, leading to the formation of O-glucuronide conjugates via direct glucuronidation. Its metabolism through cytochrome P450 enzymes (CYPs) is negligible. The principal metabolite, vadadustat-O-glucuronide, accounts for 15% of the AUC of plasma radioactivity and is produced by multiple UGT enzymes, including UGT1A1, UGT1A7, UGT1A8, and UGT1A9. A minor metabolite, vadadustat acyl glucuronide, comprises 0.047% of the total plasma radioactivity. None of vadadustat's metabolites exhibit pharmacological activity.
Mechanism of Action
Vadadustat operates as an inhibitor of hypoxia-inducible factor prolyl-hydroxylases (HIF-PHIs), enhancing the activity of hypoxia-inducible factors (HIFs) even in non-hypoxic conditions. Hypoxia-inducible factors are pivotal transcription factors that promote cellular adaptation and survival during oxygen-deficient states by regulating critical processes such as angiogenesis, cell growth, differentiation, and erythropoiesis. Under typical oxygen conditions, these factors are targeted for degradation through hydroxylation by prolyl-hydroxylase dioxygenases. By inhibiting this degradation pathway, vadadustat elevates HIF levels, which subsequently boost endogenous erythropoietin production. This process facilitates increased mobilization of iron, leading to a progressive enhancement in hemoglobin concentrations and improvement in iron metabolism. In patients suffering from anemia associated with chronic kidney disease, where normal erythropoiesis is impaired, vadadustat effectively contributes to the correction of anemia.
