What is the mechanism of action and reaction principle of dapostat?

Daprodustat is an oral HIF-PH inhibitor (Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor). Its core mechanism is derived from simulating hypoxia in the body and activating endogenous erythropoietin (EPO) production, thereby improving chronic kidney disease-related anemia (CKD-anemia). Under normal circumstances, the human body senses changes in oxygen concentration through the HIF pathway. When tissues are in a hypoxic state, HIF-α subunits escape hydroxylation and accumulate, combine with HIF-β to form a transcription complex, and activate multiple genes related to hematopoiesis and iron metabolism, including EPO, transferrin and iron transporter. In patients with chronic kidney disease, due to tubulointerstitial fibrosis and dysfunction of EPO-producing cells, activation of the HIF pathway is blocked, resulting in reduced red blood cell production.

Daprostat stabilizes HIF-α protein levels by inhibitingHIF-α degrading enzyme prolyl hydroxylase (PHD) activity, promotes the formation of functional HIF complexes in the nucleus, further promotes the synthesis of EPO in the liver and kidneys, and increases peripheral hemoglobin concentration. In addition to directly stimulating EPO production, dapoxostat can also regulate iron metabolism in the body, effectively improving functional iron deficiency in inflammatory conditions by reducing hepcidin levels in the liver, enhancing intestinal absorption and bone marrow utilization of iron. In addition, it increases transferrin saturation and serum iron levels, making it responsive even in anemic patients in an immunocompetent state.

These effects of dapocetostat are time-dependent and dose-dependent. Its half-life design allows for once-daily oral administration, reducing the inconvenience caused by traditional erythropoietin injections, and its rate of increasingHb levels is more gradual, helping to reduce adverse cardiovascular events related to rapid correction of anemia. In clinical application, the safety and effectiveness of the drug have been verified in multiple large-scale phase III trials, providing a new and more physiological solution for the treatment of renal anemia.

Reference materials:https://en.wikipedia.org/wiki/Daprodustat