Daprodustat

Daprodustat Overview

Daprodustat (chemically designated N-[(1,3-dicyclohexyl-2,4,6-trioxohexahydropyrimidin-5-yl)
carbonyl]glycine; chemical formula C19H27N3O6) is a small-molecule, oral hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor. Chemically, it belongs to the class of organic compounds known as N-acyl-alpha-amino acids within the amino acids, peptides, and analogues sub-class. Structurally, it consists of a pyrimidinetrione (barbituric acid derivative) core substituted with two N-linked cyclohexyl rings and a glycinylcarbonyl side chain.

In nephrology and hematology, Daprodustat functions as an antianemic agent and HIF prolyl hydroxylase inhibitor (ATC code B03XA07 for other antianemic preparations). Formulated as oral film-coated tablets (marketed under the trade name Jesduvroq in 1 mg, 2 mg, 4 mg, 6 mg, and 8 mg strengths), it is indicated for the treatment of anemia due to chronic kidney disease (CKD) in adults who have been receiving dialysis for at least four months. By inhibiting prolyl hydroxylase enzymes, Daprodustat mimics the physiological response to hypoxia, stimulating endogenous erythropoietin production in the kidneys and liver while enhancing intestinal iron absorption and systemic transport.

What Is Daprodustat and How Does It Work?

Daprodustat acts primarily through reversible inhibition of prolyl hydroxylase domain enzymes (PHD1, PHD2, and PHD3), leading to stabilization of HIF-1alpha and HIF-2alpha subunits and stimulation of endogenous erythropoiesis.

Its primary chemical, physiological, and hematological mechanisms include:

• HIF-Prolyl Hydroxylase Inhibition: Daprodustat acts as a potent, reversible, competitive inhibitor of EGLN1 (PHD2), EGLN2 (PHD1), and EGLN3 (PHD3) enzymes.
• HIF Stabilization & Translocation: Under normal normoxic conditions, PHD enzymes hydroxylate specific proline residues on hypoxia-inducible factor alpha subunits (HIF-1alpha and HIF-2alpha), targeting them for polyubiquitination and rapid proteasomal degradation. Inhibition of PHDs prevents hydroxylation, stabilizing HIF-alpha subunits and allowing them to translocate to the cell nucleus.
• Hypoxia Response Element (HRE) Binding: In the nucleus, HIF-alpha dimerizes with HIF-1beta and binds to HRE sequences on DNA, driving transcription of target genes.
• Endogenous Erythropoietin Generation: Activation of target genes induces physiological synthesis and release of endogenous erythropoietin (EPO) from residual renal interstitial cells and hepatocytes.
• Iron Mobilization & Utilization: HIF activation downregulates hepcidin expression while upregulating transferrin, transferrin receptor 1, and ferroportin, enhancing intestinal iron absorption and mobilizing iron stores for erythropoiesis in bone marrow.

Is Daprodustat FDA Approved?

Daprodustat was approved by the US FDA in February 2023 under the brand name Jesduvroq as the first oral HIF-PH inhibitor for adult CKD patients on dialysis. Its current approval status is FDA Approved (February 2023).

What Is Daprodustat Used For?

• Treatment of anemia due to chronic kidney disease (CKD) in adult patients who have been receiving dialysis for at least four months.
• Oral alternative to injectable erythropoiesis-stimulating agents (ESAs) such as epoetin alfa or darbepoetin alfa in dialysis settings.

Before Taking Daprodustat: Contraindications & Precautions

Do not use Daprodustat in patients with uncontrolled hypertension or in patients taking strong CYP2C8 inhibitors (such as gemfibrozil). It is not indicated and not recommended for use in patients with anemia of CKD who are not on dialysis due to an increased risk of serious cardiovascular events. Discontinue use if arterial thrombosis, severe hypertension, or hypersensitivity occurs.

Who Should Not Take Daprodustat?

• Patients with anemia due to CKD who are not on dialysis.
• Patients taking strong CYP2C8 inhibitors (e.g., gemfibrozil).
• Patients with uncontrolled, refractory hypertension.
• Individuals with known hypersensitivity to Daprodustat or formulation excipients.

Daprodustat, Pregnancy & Boxed Warning

Daprodustat carries a Boxed Warning regarding an increased risk of death, myocardial infarction, stroke, venous thromboembolism, and vascular access thrombosis. In animal reproduction studies, Daprodustat administration during organogenesis resulted in reduced fetal body weight, skeletal variations, and post-implantation loss at maternally toxic exposures. There are no adequate data on human pregnancy risks. Discontinue Daprodustat when pregnancy is recognized unless benefits outweigh potential fetal risks.

Tell Your Doctor Before Taking Daprodustat

Inform your nephrologist if you have a history of cardiovascular disease, heart failure, stroke, venous blood clots, liver disease, active malignancy, or uncontrolled high blood pressure.

Daprodustat Dosage & Administration

Formulated as oral film-coated tablets in strengths of 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, and 24 mg.

Standard Daprodustat Dosing

• Switching from an ESA or Starting Dose (Adult Dialysis Patients): Starting doses range from 1 mg to 4 mg orally once daily based on pre-treatment hemoglobin levels or prior ESA dose.
• Dose Titration: Hemoglobin levels should be evaluated every 2 to 4 weeks after starting or adjusting the dose. Adjust the dose by 1 mg to 2 mg increments to maintain target hemoglobin between 10 g/dL and 11 g/dL (do not exceed 24 mg daily).

How Daprodustat Is Administered

• Take orally once daily, with or without food.
• Tablets should be swallowed whole; do not chew, crush, or split tablets.
• May be taken without regard to phosphate binders or iron supplements.

Daprodustat Clinical Efficacy & Safety Profile

In the pivotal Phase 3 ASCEND-D trial involving over 3,800 adult patients with CKD on dialysis, oral Daprodustat demonstrated non-inferiority to parenteral erythropoiesis-stimulating agents (epoetin alfa or darbepoetin alfa) regarding mean change in hemoglobin from baseline and incidence of major adverse cardiovascular events (MACE). However, it failed to demonstrate superiority in quality of life outcomes and carries significant cardiovascular and thrombotic risks similar to traditional ESAs when target hemoglobin concentrations are exceeded.

Daprodustat Side Effects & Safety Profile

Common adverse effects include hypertension, vascular access thrombosis, diarrhea, headache, peripheral edema, and abdominal pain. Serious risks include death, myocardial infarction, stroke, deep vein thrombosis, pulmonary embolism, vascular access occlusion, severe hypertension, and potential tumor growth stimulation. Holds an FDA Black Box Warning.

Common Daprodustat Side Effects

• Vascular & Systemic: Increased blood pressure (hypertension), vascular access thrombosis, and peripheral edema.
• Gastrointestinal & Neurological: Diarrhea, abdominal pain, nausea, and headache.

Serious Daprodustat Adverse Events

• Thromboembolic Events: Myocardial infarction, ischemic stroke, deep vein thrombosis, pulmonary embolism, and arteriovenous fistula thrombosis.
• Exacerbation of Hypertension: Rapid elevations in systolic and diastolic blood pressure requiring intensification of antihypertensive therapy.
• Malignancy Risk: Potential enhancement of tumor growth due to HIF-mediated angiogenesis and cellular proliferation signaling.

Managing Daprodustat Side Effects

Monitor blood pressure at every clinical visit and manage hypertension aggressively. Withhold or reduce Daprodustat dosage if hemoglobin rises rapidly (> 1 g/dL in any 2-week period) or exceeds 11 g/dL.

Daprodustat Drug Interactions & What to Avoid

Daprodustat is metabolized primarily by CYP2C8 and to a lesser extent by CYP3A4.

Daprodustat Drug-Drug Interactions

• Strong CYP2C8 Inhibitors (e.g., Gemfibrozil): Co-administration is contraindicated because gemfibrozil significantly increases Daprodustat systemic exposure, raising toxicity risks.
• Moderate CYP2C8 Inhibitors (e.g., Clopidogrel): Increases Daprodustat exposure; reduce starting dose by half when co-administered.
• CYP2C8 Inducers (e.g., Rifampin): Decreases Daprodustat systemic exposure, potentially reducing therapeutic efficacy.

Daprodustat, Food & Alcohol

Systemic exposure is not significantly altered by food. Avoid heavy alcohol consumption to support cardiovascular and liver health during dialysis management.

Daprodustat: Missed Dose, Overdose & Storage

Take missed doses on the same day as remembered, or skip if near the next dose. Overdose causes polycythemia and thrombotic risk. Store at room temperature (15°C–25°C).

Missed Dose of Daprodustat

Take the missed tablet as soon as remembered on the same day. If it is almost time for the next scheduled dose, skip the missed tablet and resume your regular daily schedule. Do not take two doses at the same time.

Daprodustat Overdose & Emergency

Overdose causes excessive elevation of hemoglobin levels, hyperviscosity, and severe thromboembolic complications. Emergency management involves withholding Daprodustat, monitoring cardiovascular status, and considering phlebotomy if polycythemia is severe.

How to Store Daprodustat

Store film-coated tablets at controlled room temperature between 15°C and 25°C (59°F to 77°F). Protect from excessive heat and moisture. Keep in the original bottle and strictly out of reach of children.

Daprodustat Patient Management & Monitoring

Requires routine hemoglobin checks, blood pressure monitoring, and cardiovascular risk assessment.

Tests Before Starting Daprodustat

Baseline hemoglobin, serum ferritin, transferrin saturation (TSAT), blood pressure evaluation, and assessment of vascular access patency.

Monitoring During Daprodustat Treatment

Monitor hemoglobin levels every 2 weeks following initiation or dose adjustment until stable, then monthly; monitor blood pressure regularly; evaluate iron parameters (ferritin and TSAT) periodically.

Daprodustat Do’s and Don’ts

• Do take oral tablets once daily as prescribed by your nephrologist.
• Do maintain adequate iron stores (ferritin and TSAT) during therapy.
• Do not take Daprodustat if you are an anemia patient with CKD who is not on dialysis.
• Do not take concurrently with gemfibrozil.
• Do not double doses to make up for a missed tablet.

Frequently Asked Questions

References

• DrugBank Database – Daprodustat Clinical Profile (DB11682)
• Classyfire Database – N-acyl-alpha-amino acids / Carboxylic Acids Taxonomy Profile
• US FDA Prescribing Information – Jesduvroq (Daprodustat) Tablets

Legal Disclaimer

The detailed medical and chemical information provided on this specific web page is intended strictly for educational and informational purposes regarding complex pharmacological mechanisms. It absolutely does not constitute professional medical advice, medical diagnosis, or specific treatment recommendations. Always consult a licensed healthcare provider before making any personal decisions regarding complex medical conditions, medication adjustments, or dietary changes.