Jesduvroq - Drug Monograph

Introduction

Jesduvroq (daprodustat) is an oral hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor approved for the treatment of anemia associated with chronic kidney disease (CKD) in adults who have been receiving dialysis for at least three months. It represents a novel class of erythropoiesis-stimulating agents that work by mimicking the body's physiological response to hypoxia.

Mechanism of Action

Daprodustat inhibits hypoxia-inducible factor prolyl hydroxylase (HIF-PH) enzymes, which normally target HIF-α subunits for degradation under normoxic conditions. By inhibiting these enzymes, daprodustat stabilizes HIF-α, leading to increased transcription of genes involved in erythropoiesis, including erythropoietin, and iron metabolism. This results in increased red blood cell production and improved iron utilization, similar to the natural physiological response to hypoxia.

Indications

• Treatment of anemia associated with chronic kidney disease in adults who have been on dialysis for at least three months

Dosage and Administration

• Starting dose: 4 mg orally once daily
• Dose titration: Adjust based on hemoglobin response every 4 weeks
• Maintenance dose range: 1-24 mg once daily

• Hepatic impairment: No dosage adjustment required
• Renal impairment: Specifically indicated for dialysis-dependent CKD patients
• Elderly: No specific dosage adjustment recommended

• Administer once daily with or without food
• Tablets should be swallowed whole

Pharmacokinetics

• Peak plasma concentrations achieved in 1-3 hours
• Oral bioavailability approximately 70%
• Food does not significantly affect exposure

• Protein binding: 97%
• Steady state achieved within 4 days
• Volume of distribution: ~16 L

• Primarily metabolized via glucuronidation (UGT1A9, UGT1A1)
• Minor metabolism via CYP2C8 and CYP3A4

• Half-life: ~4 hours
• Excretion: Primarily fecal (58%) and renal (22%)
• Dialysis: Not expected to be significantly removed by hemodialysis

Contraindications

• Hypersensitivity to daprodustat or any component of the formulation
• Uncontrolled hypertension
• History of myocardial infarction, stroke, or unstable angina within 3 months prior to initiation

Warnings and Precautions

• Increased risk of death, myocardial infarction, stroke, venous thromboembolism, and thrombosis of vascular access

• Hypertension: May exacerbate hypertension; monitor and control blood pressure
• Seizures: Has been associated with seizures
• Malignancy: Theoretical risk of promoting tumor growth due to HIF stabilization
• Gastrointestinal erosion: May increase risk of gastrointestinal erosion
• Hepatic impairment: Use with caution in severe hepatic impairment

Drug Interactions

• Gemfibrozil: May increase daprodustat exposure
• Clopidogrel: May increase daprodustat exposure

• Atazanavir: May increase daprodustat exposure

• Rifampin: May decrease daprodustat exposure

Adverse Effects

• Hypertension (28%)
• Dyspnea (24%)
• Diarrhea (19%)
• Bronchitis (14%)
• Headache (13%)
• Nausea (12%)
• Cough (11%)
• Dizziness (10%)

• Thrombotic vascular events
• Hypertension crisis
• Seizures
• Gastrointestinal erosion

Monitoring Parameters

• Hemoglobin level
• Iron studies (ferritin, TSAT)
• Blood pressure
• Cardiovascular risk assessment

• Hemoglobin: Weekly until stable, then monthly
• Blood pressure: Regularly
• Iron parameters: Every 3 months
• Signs/symptoms of thrombosis: Ongoing assessment
• Liver function tests: Periodically

Patient Education

• Take medication exactly as prescribed, once daily
• Do not adjust dosage without medical supervision
• Report any signs of blood clots (chest pain, shortness of breath, leg swelling)
• Monitor and report blood pressure readings regularly
• Report any seizures, severe headaches, or gastrointestinal symptoms
• Inform all healthcare providers about Jesduvroq use
• Keep all follow-up appointments for laboratory monitoring
• Store at room temperature away from moisture

References

1. FDA Approval Package: Jesduvroq (daprodustat) tablets. FDA.gov. 2023. 2. Singh AK, Carroll K, Perkovic V, et al. Daprodustat for the Treatment of Anemia in Patients Undergoing Dialysis. N Engl J Med. 2021;385(25):2325-2335. 3. Jesduvroq [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2023. 4. Provenzano R, Besarab A, Wright S, et al. Roxadustat for Anemia in Patients with Kidney Disease Not Receiving Dialysis. N Engl J Med. 2019;381(11):1001-1010. 5. Chen N, Hao C, Liu BC, et al. Roxadustat Treatment for Anemia in Patients Undergoing Long-Term Dialysis. N Engl J Med. 2019;381(11):1011-1022. 6. ClinicalTrials.gov: ASCEND-D and ASCEND-ND trials. NCT02879305 and NCT02876835.