Daprotab

Approved Indications:

• Anemia of Chronic Kidney Disease (CKD):
• Treatment of anemia in adult patients with CKD, including those on dialysis and those not on dialysis.

Clinically Accepted Off-label Uses:

• Management of anemia in other chronic conditions associated with impaired erythropoiesis (investigational/off-label).

Adults:

• For CKD Patients Not on Dialysis:
• Initial oral dose: 4 mg once daily.
• Dose may be adjusted every 4 weeks based on hemoglobin response, within a range of 1 to 8 mg daily.
• For CKD Patients on Dialysis:
• Initial oral dose: 6 mg once daily.
• Dose adjustments as above.

Pediatrics:

• Safety and efficacy not established; not recommended.

Elderly:

• No specific dose adjustment; monitor hemoglobin and renal function carefully.

Renal and Hepatic Impairment:

• No dose adjustment necessary in mild to moderate hepatic impairment.
• Patients with severe hepatic impairment have not been studied.

Administration:

• Oral tablets, once daily with or without food.

Daprodustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI). It stabilizes HIF transcription factors by inhibiting prolyl hydroxylase enzymes that normally target HIF-α subunits for degradation under normoxic conditions. Stabilized HIF activates transcription of erythropoietin (EPO) and other genes involved in iron metabolism, promoting increased endogenous erythropoiesis. This enhances red blood cell production and improves anemia in CKD patients by mimicking physiological responses to hypoxia.

Absorption:

• Rapidly absorbed; peak plasma concentrations occur approximately 1 to 2 hours post-dose.
• Absolute bioavailability not precisely established.

Distribution:

• Moderate plasma protein binding (~95%).

Metabolism:

• Extensively metabolized primarily by CYP2C8; minor contribution by CYP3A4.

Elimination:

• Excreted mainly via feces (approximately 74%) and urine (approximately 20%) as metabolites.
• Terminal elimination half-life about 4 hours.

• Pregnancy:
• No FDA pregnancy category assigned; animal studies suggest potential fetal risk. Use only if benefits justify risks.
• Lactation:
• Data unavailable on excretion in human milk; breastfeeding not recommended during treatment.

• Primary Class: Anemia treatment agent
• Subclass: Hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI)

• Known hypersensitivity to daprodustat or any excipients.
• Uncontrolled hypertension.
• Active malignancy (due to theoretical risk of tumor progression).
• Pregnancy and breastfeeding.

• Cardiovascular Risk: Monitor blood pressure; hypertension may worsen.
• Thromboembolic Events: Increased risk; use cautiously in patients with history of thrombosis.
• Tumor Promotion: Potential risk due to HIF pathway activation; avoid use in active cancer.
• Iron Status: Monitor iron parameters; supplement iron if deficient to optimize erythropoiesis.
• Hepatic Impairment: Use cautiously in severe hepatic impairment.
• Hemoglobin Levels: Avoid excessive erythropoiesis; target hemoglobin according to guidelines to reduce cardiovascular risk.

Common:

• Diarrhea
• Nausea
• Headache
• Hypertension
• Dizziness

Serious/Rare:

• Thromboembolism (deep vein thrombosis, pulmonary embolism)
• Elevated liver enzymes
• Allergic reactions

• CYP2C8 Inhibitors (e.g., gemfibrozil): May increase daprodustat plasma concentrations, increasing risk of adverse effects.
• CYP2C8 Inducers (e.g., rifampin): May reduce daprodustat efficacy by decreasing plasma levels.
• Antihypertensive Agents: Monitor blood pressure due to potential additive effects.
• Iron Supplements: No direct interaction, but iron monitoring essential during treatment.

• Recent anemia management guidelines recommend HIF-PHIs like daprodustat as alternatives to erythropoiesis-stimulating agents (ESAs) in CKD anemia.
• Updated safety data emphasize cardiovascular monitoring and individualized hemoglobin targets.
• Ongoing studies assessing long-term safety and cancer risk.

• Store at 20°C to 25°C (68°F to 77°F).
• Protect from moisture and light.
• Keep tablets in original container tightly closed.
• Do not freeze.
• Keep out of reach of children.