Daprodustat (Jesduvroq)
daprodustat — first-in-class oral HIF prolyl hydroxylase inhibitor approved in the US
Indications for Daprodustat
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Anemia due to CKD (patients on dialysis for ≥4 months) | Adults only | Monotherapy (not with ESAs) | FDA Approved |
Daprodustat is the first oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) approved in the United States (February 2023). By reversibly inhibiting HIF prolyl hydroxylase enzymes (PHD1, PHD2, PHD3), it stabilizes HIF-1α and HIF-2α transcription factors, leading to increased endogenous erythropoietin production and enhanced iron absorption — mimicking the physiological response to high-altitude hypoxia. In the ASCEND-D trial (n=2964), daprodustat was noninferior to ESAs for both hemoglobin efficacy and cardiovascular safety in dialysis patients. Notably, the FDA advisory committee voted 13–3 in favour of the dialysis indication but voted 11–5 against approval for the non-dialysis CKD population, and daprodustat is currently NOT approved for patients not on dialysis in the US.
Daprodustat is NOT indicated for: patients not on dialysis; as a substitute for emergency RBC transfusion; or in patients who require immediate correction of anemia. Not studied in patients with active malignancy or severe hepatic impairment. Must not be used concurrently with ESAs.
Dosing for Daprodustat
ESA-Naive Patients (Not Currently on an ESA)
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Hb <9 g/dL | 4 mg PO once daily | Titrate by 1 dose level q4wk | 8 mg once daily | Must be on dialysis ≥4 months. Do not target Hb >11 g/dL Dose levels: 1 → 2 → 4 → 6 → 8 mg |
| Hb 9 to ≤10 g/dL | 2 mg PO once daily | Titrate by 1 dose level q4wk | 8 mg once daily | Adjust based on Hb rate of rise, rate of decline, and variability Reduce if Hb ↑ >1 g/dL in 2 wks or >2 g/dL in 4 wks |
| Hb >10 g/dL | 1 mg PO once daily | Titrate by 1 dose level q4wk | 8 mg once daily | Lowest starting dose; used when Hb is closer to target Interrupt if Hb exceeds 12 g/dL; restart 1 level lower when in range |
Patients Switching from an ESA
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Switching from ESA (dose-based conversion) | Based on PI conversion table (1–8 mg) | Titrate by 1 dose level q4wk | 8 mg once daily | Starting dose mapped from prior weekly ESA dose (see PI Table 2). For SC epoetin alfa: multiply SC dose/wk by 1.42 to get IV equivalent before conversion Discontinue ESA before starting daprodustat |
| Moderate hepatic impairment (Child-Pugh B) | Reduce starting dose by 50% | Standard titration | 8 mg once daily | Exception: do not reduce if starting dose is already 1 mg Severe hepatic impairment (Child-Pugh C): not studied, not recommended |
| With moderate CYP2C8 inhibitor (e.g., clopidogrel) | Reduce starting dose by 50% | Adjust based on Hb | 8 mg once daily | Exception: do not reduce if starting dose is already 1 mg. Monitor Hb when starting or stopping CYP2C8 inhibitor Strong CYP2C8 inhibitors (gemfibrozil): CONTRAINDICATED |
Adjust dose no more than once every 4 weeks. Change by 1 dose level at a time (dose levels: 1 mg → 2 mg → 4 mg → 6 mg → 8 mg). Reduce dose if Hb rises >1 g/dL in 2 weeks or >2 g/dL in 4 weeks, or if Hb exceeds 11 g/dL. If Hb exceeds 12 g/dL, interrupt therapy and restart at 1 dose level lower once Hb is within the target range. Discontinue if no clinically meaningful Hb increase is achieved after 24 weeks of therapy. Daprodustat also alters iron metabolism: it increases transferrin and total iron binding capacity while decreasing ferritin, transferrin saturation, and hepcidin levels, which may improve iron mobilisation but can mask iron deficiency on standard laboratory markers.
Pharmacology of Daprodustat
Mechanism of Action
Daprodustat reversibly inhibits all three isoforms of HIF prolyl hydroxylase (PHD1, PHD2, PHD3). Under normal oxygen conditions, these enzymes hydroxylate HIF-α subunits, marking them for rapid proteasomal degradation via the von Hippel-Lindau (VHL) ubiquitin ligase pathway. By blocking this oxygen-sensing step, daprodustat stabilizes HIF-1α and HIF-2α, which then dimerise with HIF-β and translocate to the nucleus, activating transcription of erythropoietin and other genes involved in erythropoiesis, iron transport (transferrin, ferroportin), and iron absorption. This mechanism mimics the natural physiological adaptation to high altitude. Endogenous erythropoietin levels increase in a dose-dependent manner within 6 to 8 hours of administration, with reticulocyte counts peaking between 7 and 15 days, and subsequent hemoglobin increases occurring within 2 to 6 weeks.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Rapidly absorbed; Tmax 1–4 h. Absolute bioavailability 65%. Food does not significantly alter exposure. Dose-proportional across 1–8 mg. Steady-state within 24 h. | Can be taken with or without food, including with dialysis meals. Rapid onset allows once-daily dosing with consistent exposure. |
| Distribution | Vd 14.3 L (IV, healthy). Protein binding >99% (albumin). Blood:plasma ratio 1.23 (approximately equal distribution between plasma and blood cells). | Highly protein-bound; not significantly removed by hemodialysis. Does not penetrate the CNS. |
| Metabolism | Primarily CYP2C8 (95%), minor CYP3A4 (5%). No induction of CYP1A2, 2B6, or 3A4. Does not inhibit major CYP enzymes or P-gp. | CYP2C8 is the critical metabolic pathway. Gemfibrozil (strong CYP2C8 inhibitor) causes 18.6-fold AUC increase — CONTRAINDICATED. Clopidogrel (moderate): 4-fold AUC increase — reduce dose by 50%. |
| Elimination | t½: 1–4 h (healthy); ~7 h (CKD on dialysis day); ~18.9 h (CKD non-dialysis day). <0.1% excreted unchanged in urine. Not removed by dialysis. | Longer half-life on non-dialysis days (slower metabolite clearance in CKD). Renal impairment does not affect parent drug exposure; metabolite exposure is higher in CKD patients. |
Side Effects of Daprodustat
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Hypertension | ≥10% | Most common adverse reaction. New or worsening hypertension may occur. Monitor BP and adjust antihypertensive therapy. |
| Thrombotic vascular events (composite) | ≥10% | Includes MI, stroke, DVT, PE, vascular access thrombosis. Subject of FDA boxed warning. Noninferiority to ESAs demonstrated in ASCEND-D. |
| Abdominal pain | ≥10% | More common than with ESAs. Investigate for GI erosion if persistent. |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Dizziness | ≥5% | May be related to blood pressure changes during treatment. |
| Hypersensitivity reactions | ≥5% | Includes rash, urticaria, and dermatitis. Discontinue if severe. |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| MACE (death, MI, stroke) | 25.2% daprodustat vs 26.7% ESA (ASCEND-D, median 2.5 yr) | Throughout treatment; risk increases with Hb >11 g/dL | FDA BOXED WARNING. Noninferiority met (HR 0.93, 95% CI 0.81–1.07). Use lowest dose to avoid transfusion. Do not target Hb >11 g/dL. |
| Venous thromboembolism (DVT, PE) | Increased risk (class effect) | During treatment period | FDA BOXED WARNING. Monitor for DVT/PE symptoms. Consider thromboprophylaxis in high-risk patients. |
| Hospitalization for heart failure | Increased in patients with HF history | Variable | Increased risk in patients with prior heart failure. Monitor fluid status closely. |
| Gastrointestinal erosion and bleeding | Uncommon | Variable; assess GI risk factors before starting | Consider history of peptic ulcer, concomitant NSAIDs/anticoagulants, smoking, and alcohol. Investigate abdominal pain promptly. |
| Potential malignancy risk (theoretical) | Unknown; long-term data pending | Theoretical concern with HIF pathway activation | HIF-1 involved in tumour angiogenesis and growth. Not studied in patients with active malignancy. Avoid in patients with cancer within 2 years. |
Daprodustat alters iron homeostasis through HIF-mediated mechanisms: it increases serum transferrin and total iron binding capacity (TIBC) while decreasing serum ferritin, transferrin saturation (TSAT), and hepcidin. These changes reflect enhanced iron mobilisation and utilisation for erythropoiesis. However, the decrease in ferritin and TSAT can mask true iron deficiency if standard laboratory thresholds are applied without adjustment. Clinicians should maintain awareness that iron parameters may trend differently than expected during HIF-PHI therapy.
Drug Interactions with Daprodustat
Daprodustat is primarily metabolised by CYP2C8, making it highly susceptible to interactions with CYP2C8 inhibitors and inducers. Unlike ESAs (which are biological proteins with no CYP interactions), daprodustat has clinically significant pharmacokinetic drug interactions that require careful attention.
Monitoring for Daprodustat
- HemoglobinWeekly until stable; then at least q4wk
RoutineDo not target Hb >11 g/dL. Reduce dose if Hb rises >1 g/dL in 2 wks or >2 g/dL in 4 wks. Interrupt if Hb >12. Discontinue if no meaningful increase after 24 weeks. - Blood PressureBaseline and each visit
RoutineNew or worsening hypertension may occur. Adjust antihypertensive therapy as needed. Uncontrolled hypertension is a contraindication. - Iron StudiesBefore starting; periodically during therapy
RoutineTSAT >20% and ferritin >100 ng/mL required before initiation. Daprodustat decreases ferritin and TSAT via HIF-mediated iron mobilisation — interpret cautiously. - Liver FunctionBaseline (to determine dose); periodically
RoutineModerate hepatic impairment (Child-Pugh B) requires 50% dose reduction. Severe impairment (Child-Pugh C) is not studied — use not recommended. - GI SymptomsEach visit; promptly if abdominal pain
Trigger-basedRisk of GI erosion and bleeding. Consider peptic ulcer history, concomitant NSAIDs/anticoagulants, smoking, and alcohol use. Investigate persistent abdominal pain. - CYP2C8 InteractionsAt each medication change
Trigger-basedReview concomitant medications for CYP2C8 inhibitors (gemfibrozil contraindicated) and inducers (rifampin). Adjust dose when starting or stopping interacting drugs.
Contraindications & Cautions for Daprodustat
Absolute Contraindications
- Strong CYP2C8 inhibitors (e.g., gemfibrozil): Causes 18.6-fold increase in daprodustat exposure. Concomitant use is contraindicated.
- Uncontrolled hypertension: Must achieve adequate BP control before initiation.
Relative Contraindications (Specialist Input Recommended)
- Active malignancy or history of malignancy within 2 years: HIF-1 pathway is implicated in tumour angiogenesis and growth. Not studied in patients with cancer.
- Severe hepatic impairment (Child-Pugh C): Pharmacokinetics not studied; use not recommended.
- Active GI bleeding, peptic ulcer disease, or GI erosion: Risk of GI erosion and bleeding with daprodustat.
Use with Caution
- History of heart failure: Increased risk of hospitalisation for heart failure with daprodustat.
- Concomitant moderate CYP2C8 inhibitors (e.g., clopidogrel): Requires 50% dose reduction at initiation.
- Pregnancy: May cause fetal harm based on animal studies (post-implantation loss, reduced fetal weight). Insufficient human data.
- Lactation: Breastfeeding not recommended during treatment and for 1 week after last dose.
Daprodustat increases the risk of thrombotic vascular events, including major adverse cardiovascular events (MACE). Targeting a hemoglobin level greater than 11 g/dL is expected to further increase the risk of death and arterial and venous thrombotic events, as occurs with ESAs. No trial has identified a hemoglobin target level, dose of daprodustat, or dosing strategy that does not increase these risks. In ASCEND-D, MACE occurred in 25.2% of daprodustat patients vs 26.7% of ESA patients over a median 2.5 years (HR 0.93, 95% CI 0.81–1.07), demonstrating noninferiority but not superiority to ESAs. Prescribers must use the lowest dose of daprodustat sufficient to reduce the need for RBC transfusions.
Patient Counselling for Daprodustat
Purpose of Therapy
Daprodustat is a daily tablet prescribed to treat anaemia caused by chronic kidney disease. It works by stimulating the body to produce its own erythropoietin — the hormone that tells the bone marrow to make more red blood cells. This is a different approach from injectable erythropoietin treatments that have been used for the past three decades.
How to Take
Take one tablet by mouth once a day, with or without food. You can take it at any time of day, but try to be consistent. Store tablets at room temperature (20–25°C). Do not take this medication together with an injectable erythropoietin (ESA) treatment.
Sources
- Jesduvroq (daprodustat) tablets, for oral use. Full prescribing information. GlaxoSmithKline. February 2023. DailyMedPrimary source for all dosing, boxed warning, adverse reactions, pharmacokinetics, contraindications, and CYP2C8 interaction data.
- FDA Drug Trials Snapshots: Jesduvroq. U.S. Food and Drug Administration. February 2024. FDAFDA summary of ASCEND-D trial design, demographics, efficacy and safety results including MACE data.
- Singh AK, Carroll K, Perkovic V, et al. Daprodustat for the treatment of anemia in patients undergoing dialysis (ASCEND-D). N Engl J Med. 2021;385(25):2325–2335. doi:10.1056/NEJMoa2113379Pivotal trial (n=2964): daprodustat noninferior to ESA for Hb efficacy (Hb change 0.28 vs 0.10 g/dL) and CV safety (MACE HR 0.93). Basis of FDA approval.
- Singh AK, Carroll K, McMurray JJV, et al. Daprodustat for the treatment of anemia in patients not undergoing dialysis (ASCEND-ND). N Engl J Med. 2021;385(25):2313–2324. doi:10.1056/NEJMoa2113380ASCEND-ND (n=3872): daprodustat noninferior to darbepoetin alfa in non-dialysis CKD. FDA did not approve this indication (advisory committee voted 11–5 against).
- Johansen KL, Cobitz AR, Singh AK, et al. The ASCEND-NHQ randomized trial: positive effects of daprodustat on hemoglobin and quality of life in non-dialysis CKD. Kidney Int. 2023;103(6):1150–1159. doi:10.1016/j.kint.2023.02.028Placebo-controlled trial (n=614): daprodustat superior to placebo for Hb increase (1.40 g/dL difference) and SF-36 Vitality score (5.4 point improvement) in non-dialysis CKD.
- KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. Kidney Int Suppl. 2012;2(4):279–335. doi:10.1038/kisup.2012.37KDIGO 2012 anemia guideline: ESA initiation when Hb <10; do not exceed Hb 11.5; iron evaluation before and during therapy. Applicable framework for HIF-PHI use.
- Bohlius J, Bohlke K, Castelli R, et al. ASCO/ASH Clinical Practice Guideline Update: Management of Cancer-Associated Anemia. J Clin Oncol. 2019;37(15):1336–1351. doi:10.1200/JCO.18.02142ASCO/ASH 2019: relevant for understanding ESA safety context; HIF-PHIs not addressed in this guideline but subject to same Hb target principles.
- Dhillon S. Daprodustat: first approval. Drugs. 2020;80(14):1491–1497. doi:10.1007/s40265-020-01384-yReview of daprodustat mechanism (HIF-PHI class), development history, Japan approval (June 2020), and initial clinical pharmacology data.
- Sanghani NS, Haase VH. Hypoxia-inducible factor activators in renal anemia: current clinical experience. Adv Chronic Kidney Dis. 2019;26(4):253–266. doi:10.1053/j.ackd.2019.04.004Comprehensive review of HIF-PHI class mechanism, iron metabolism effects, and theoretical malignancy concerns with HIF pathway activation.
- Meadowcroft AM, Cizman B, Engel B, et al. Daprodustat for anemia: a 24-week, open-label, randomized controlled trial in participants on hemodialysis. Clin Kidney J. 2019;12(1):139–148. doi:10.1093/ckj/sfy014Phase 2 study in hemodialysis patients providing early PK data, dose-response, and safety characterisation of daprodustat.
- Shinfuku A, Shimazaki T, Fujiwara M, et al. Pharmacokinetics and pharmacodynamics of daprodustat in Japanese patients with renal anemia on hemodialysis and peritoneal dialysis. Clin Pharmacol Drug Dev. 2021;10(3):249–258. doi:10.1002/cpdd.866PK study confirming half-life differences between dialysis days (~7 h) and non-dialysis days (~18.9 h) in HD patients; PD patients showed similar PK.
- Chung EY, Palmer SC, Saglimbene VM, et al. Erythropoiesis-stimulating agents for anaemia in adults with chronic kidney disease: a network meta-analysis. Cochrane Database Syst Rev. 2023;2(2):CD010590. doi:10.1002/14651858.CD010590.pub22023 Cochrane network meta-analysis: contextualises HIF-PHIs within the broader ESA landscape for CKD anemia management.
- FDA Drug Safety Communication: Information on Erythropoiesis-Stimulating Agents (ESAs). U.S. FDA. Updated 2017. FDA ESA PageESA class-wide safety context: boxed warning history, REMS, and Hb target recommendations applicable to all erythropoiesis-stimulating therapies including HIF-PHIs.