Chronic kidney disease (CKD)-associated anemia, driven by erythropoietin (EPO) deficiency and iron dysregulation, significantly impacts patient survival and quality of life. Conventional therapies like erythropoiesis-stimulating agents (ESAs) face limitations including injection dependency, cardiovascular risks, and iron intolerance. Vadadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), offers a novel mechanism by stabilizing HIF-α subunits to enhance endogenous EPO production, improve iron utilization, and promote erythropoiesis. Pharmacokinetically, Vadadustat exhibits rapid absorption (peak: 2–3 hours), dose-proportional exposure, minimal accumulation, and 99.5% plasma protein binding, with adjustments recommended in dialysis-dependent CKD due to reduced clearance. Phase III clinical trials demonstrate non-inferiority of Vadadustat versus Darbepoetin Alfa in maintaining target hemoglobin levels across dialysis-dependent (DD-CKD) and non-dialysis-dependent (NDD-CKD) populations. However, while Vadadustat met cardiovascular safety endpoints in DD-CKD (INNO2VATE trials), it showed a higher major adverse cardiovascular event (MACE) risk in NDD-CKD (HR: 1.17; 95% CI: 1.01–1.36). Common adverse events include hypertension (14%), gastrointestinal disturbances (13%), and thrombosis. Drug interactions with oral iron, OAT3 inhibitors (e.g., allopurinol), and BCRP substrates require monitoring. Approved for adults with dialysis-dependent CKD (≥3 months duration), Vadadustat provides an effective oral alternative to ESAs, with potential advantages in iron mobilization and flexible thrice-weekly dosing. Future studies should address long-term cardiovascular safety in non-dialysis populations.
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