Indications
Roxadustat is prescribed for the treatment of symptomatic anemia in adult patients suffering from chronic kidney disease (CKD). It addresses the underlying anemia to alleviate symptoms associated with this condition.
Pharmacodynamics
Roxadustat acts in a dose-dependent manner to enhance iron bioavailability, thereby facilitating increased hemoglobin synthesis and expansion of red blood cell volume. In patients with non-dialysis-dependent CKD, it has demonstrated the ability to sustain hemoglobin levels for as long as two years. Its efficacy in achieving hemoglobin response is comparable to that of erythropoietin-stimulating agents. Additionally, Roxadustat has been observed to reduce cholesterol levels from baseline, irrespective of concurrent treatment with statins or other lipid-lowering medications.
Absorption
The pharmacokinetics of Roxadustat reveal that its plasma exposure, indicated by the area under the curve (AUC) and maximum concentration (Cmax), increases proportionally with dosage within its therapeutic range. When administered thrice weekly, the drug reaches steady-state plasma concentrations within one week (after three doses) with minimal accumulation. In a fasting state, peak plasma concentrations are typically achieved approximately two hours post-dosing. While taking Roxadustat with food can reduce the Cmax by 25%, it does not alter the AUC compared to fasting conditions.
Metabolism
In terms of its metabolic pathway, Roxadustat is a substrate for the enzymes CYP2C8 and UGT1A9, undergoing conversion primarily to hydroxy-roxadustat and roxadustat O-glucuronide. In human plasma, the unchanged form of Roxadustat serves as the major circulating component, with metabolites constituting less than 10% of the total drug-related material exposure. No unique metabolites have been identified in humans, although roxadustat O-glucuronide has been detected in urine samples.
Mechanism of Action
Roxadustat functions as a reversible and potent inhibitor of hypoxia-inducible factor-prolyl hydroxylase (HIF-PHD) enzymes, thereby playing a pivotal role in the treatment of anemia, particularly in the context of chronic kidney disease (CKD). By inhibiting HIF-PHD, roxadustat facilitates the accumulation of functional hypoxia-inducible factor (HIF), which subsequently stimulates the production of endogenous erythropoietin (EPO) and promotes erythropoiesis. This mechanism effectively enhances plasma EPO levels and indirectly suppresses hepcidin, a protein that regulates iron and is typically elevated during inflammatory states in CKD patients. Further, roxadustat influences iron metabolism by upregulating iron transporter proteins, leading to increased serum transferrin, enhanced intestinal iron absorption, and the mobilization of stored iron. These combined actions result in improved iron bioavailability, elevated hemoglobin production, and increased red blood cell mass in patients with anemia associated with both dialysis-dependent and dialysis-independent CKD.
