Daprodustat increases erythropoietin production, leading to an increase in the production of red blood cells.
In February 2023, the FDA approved daprodustat (Jesduvroq) for the treatment of anemia due to chronic kidney disease (CKD) in adults receiving hemodialysis for at least 4 months.1 Daprodustat is the first oral treatment approved for use in this patient population. This medication reversibly inhibits hypoxia-inducible factor (HIF) propyl hydroxylase enzymes, producing an increase in transcription factors and increased transcription of the genes that respond to HIFs. Through this mechanism, daprodustat increases production of erythropoietin and increases red blood cell production.2,3
Daprodustat efficacy was demonstrated through a phase 3, randomized, noninferiority, open label clinical trial, ASCEND-D (NCT02879305). The primary trial outcomes include the mean change in hemoglobin from baseline to the evaluation period and the first occurrence of a major adverse cardiovascular event (MACE). Eligible participants received hemodialysis for a minimum of 90 days and an erythropoiesis-stimulating agent (ESA) for a minimum of 6 weeks, and at baseline had a hemoglobin level between 8 g/dL and 12 g/dL, serum ferritin level greater than 100 ng/mL, and transferrin saturation greater than 20%.
Participants who met all inclusion criteria, including requirements for medication adherence during a 4-week placebo run-in phase, were randomly assigned to either continue ESA therapy or to discontinue ESA therapy and initiate daprodustat; doses were dependent on the previous ESA dose. Dose adjustments were allowed in both groups to target a hemoglobin level of 10 g/dL to 11 g/dL.
The study cohort included 2964 participants randomly assigned to a study group. The mean change in hemoglobin level from baseline to evaluation period was 0.28 ± 0.02 g/dL in the daprodustat group and 0.10 ± 0.02 g/dL in the ESA therapy group (0.18 g/dL difference; 95% CI, 0.12-0.24). Within the daprodustat group, 25.5% experienced a first MACE vs 26.7% in the ESA group (HR, 0.93; 95% CI, 0.81-1.07). Both primary outcomes met the preestablished margin for noninferiority. Overall, daprodustat treatment was not inferior to ESA therapy in patients with anemia due to CKD undergoing hemodialysis.
Daprodustat carries a boxed warning for an increased risk of death due to thrombotic events. In ASCEND-D, 19% of those in the daprodustat group discontinued treatment due to an adverse reaction to the drug. Common adverse effects associated with daprodustat include hypertension, thrombosis, abdominal pain, increased risk of hospitalization for heart failure, worsening hypertension, and gastrointestinal erosion. Daprodustat is not indicated for patients with uncontrolled hypertension.
It is essential to monitor blood pressure and adjust antihypertensive therapy as needed during daprodustat therapy. Careful consideration of a patient’s history of gastrointestinal erosion, peptic ulcer disease, concomitant medications, smoking status, and alcohol use is warranted. Daprodustat has not been studied in patients with cancer or with severe hepatic disease and should not be used in these patient populations. Coadministration of strong inhibitors of CYP2C8 and daprodustat is contraindicated due to increased exposure to daprodustat.
Daprodustat is available as 1-mg, 2-mg, 4-mg, 6-mg, or 8-mg tablets. Ferritin status and liver tests must be monitored. A patient’s starting dose is dependent on their current dose of an ESA. If the patient is not currently taking an ESA, the daprodustat starting dose is dependent on the patient’s current hemoglobin level. Dose reduction is necessary for patients with moderate hepatic disease or who are taking concomitant moderate CYP2C8 inhibitors. Hemoglobin levels should be monitored every 2 weeks for the first month, then monthly during therapy. Dose adjustments should occur no more frequently than once per month to reduce the need for blood transfusions and a target level of hemoglobin less than 11 g/dL.
Kathryn Wheeler, PharmD, BCPS, is the associate dean of academic affairs and an associate clinical professor of pharmacy practice in the Department of Pharmacy Practice at the University of Connecticut School of Pharmacy in Storrs.