Daprodustat is an oral hypoxia-inducible factor prolyl hydroxylase (HIF PH) inhibitor indicated for the treatment of anemia due to chronic kidney disease in adults who have been receiving dialysis for at least 4 months. Daprodustat has not been shown to improve quality of life, fatigue, or well-being. Daprodustat is not indicated as a substitute for red blood cell transfusions in persons who require immediate correction of anemia or for the treatment of anemia in chronic kidney disease in persons not receiving dialysis. Safety and efficacy of daprodustat was evaluated in a randomized, sponsor-blind, active-controlled, global, multicenter, event-driven non-inferiority clinical trial. The primary safety and efficacy outcome was the mean change in hemoglobin from baseline to the evaluation period and time to first major cardiac event (MACE), defined as all-cause mortality, non-fatal myocardial infarction, or non-fatal stroke; non-inferiority of daprodustat in comparison to recombinant human erythropoietin was achieved. Daprodustat is associated with an increased risk of thrombotic vascular events, including MACE. No trial has identified a hemoglobin target concentration, daprodustat dose, or dosing strategy that does not increase these risks.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-Administer without regard to the timing or type of dialysis.
-Administer with or without food, and without regard to concomitant administration of iron or phosphate binders.
-Swallow tablets whole; do not cut, crush, or chew daprodustat tablets.
-Missed dose: If a dose of daprodustat is missed, administer the dose as soon as possible. If it is the same day as the next scheduled dose, skip the missed dose and administer the next dose at the usual time. Do not administer double doses to make-up for a missed dose.
Daprodustat increases the risk of arterial and venous thrombotic events, that may be fatal, including myocardial infarction, stroke, venous thromboembolism, and vascular access thrombosis. Fatal and non-fatal thrombotic vascular events were observed in 9.8 per 100 person years (PY) of daprodustat-treated subjects compared to 11.7 per 100 PY of recombinant human erythropoietin-treated subjects. Vascular access thrombosis occurred in 5 per 100 PY of daprodustat-treated subjects vs. 6.3 per 100 PY of recombinant human erythropoietin-treated subjects. Myocardial infarction and stroke occurred in 3.4 per 100 PY and 1.2 per 100 PY, respectively in daprodustat-treated subjects compared to 4.1 per 100 PY and 1.5 per 100 PY, respectively in recombinant human erythropoietin-treated subjects. Deep vein thrombosis and pulmonary embolism were observed in 0.7 per 100 PY and 0.3 per 100 PY, respectively in daprodustat-treated subjects compared to 0.6 per 100 PY and 0.4 per 100 PY, respectively in recombinant human erythropoietin-treated subjects. Clinical trials have not identified a target hemoglobin concentration, daprodustat dose, or dosing strategy that does not increase the risk of thrombotic vascular events. Use the lowest dose of daprodustat that is sufficient to reduce the need for red blood cell transfusions. Adhere to dosing and hemoglobin monitoring recommendations to avoid excessive erythropoiesis. Advise persons to seek immediate medical attention if they develop signs or symptoms of myocardial infarction, stroke, venous thromboembolism, or thrombosis of vascular access; evaluate and manage promptly if these occur. Due to the effects on erythropoiesis, abuse of daprodustat may be seen in athletes. Misuse of medications that increase erythropoiesis, such as daprodustat, by healthy persons may cause development of polycythemia which can be associated with life-threatening cardiovascular complications (e.g., stroke, myocardial infarction, and thromboembolism).
Hospitalization for heart failure was reported in 7.5% (3.3 per 100 person years [PY]) of daprodustat-treated subjects compared to 6.8 % (3 per 100 PY) of recombinant human erythropoietin-treated subjects. Advise persons of the signs and symptoms of heart failure and to immediately report any worsening symptoms to their health care provider.
Worsening of hypertension occurred in 24% (12 per 100 person years [PY]) of both daprodustat and recombinant human erythropoietin-treated subjects in a clinical trial. Serious worsening of hypertension occurred in 3.1% of subjects receiving daprodustat or recombinant human erythropoietin. Hypertensive crisis, including hypertensive encephalopathy and seizures, has also been reported in persons receiving daprodustat. Periodically monitor blood pressure and adjust or initiate anti-hypertensive therapy as needed. Dizziness was reported in 7% of subjects treated with daprodustat in a clinical trial.
Gastric or esophageal erosions (i.e., esophageal ulceration) occurred in 5.7% (2.5 per 100 person years [PY]) of daprodustat-treated subjects compared to 6.6% (2.9 per 100 PY) of recombinant human erythropoietin-treated subjects in a clinical trial. Serious erosions, including GI bleeding and the need for red blood cell transfusions, were reported in 3.6% of daprodustat-treated subjects compared to 3.1% of recombinant human erythropoietin-treated subjects. Advise persons of the signs and symptoms of gastric and esophageal erosions and gastrointestinal bleeding and to seek medical care if these occur. Abdominal pain was reported in 11% of daprodustat-treated subjects in a clinical trial.
New primary malignancy was reported in 4.4% (1.9 per 100 person years [PY]) of daprodustat-treated subjects compared to 5.2% (2.3 per 100 PY) of recombinant human erythropoietin-treated subjects in a clinical trial. Evidence of increased carcinogenicity was not observed in animal studies. Hypoxia inducible factor (HIF)-1 concentrations may be associated with unfavorable effects on cancer growth.
Hypersensitivity reactions defined as rash, urticaria, and dermatitis occurred in 7% of daprodustat-treated subjects in a clinical trial.
Avoid use of daprodustat in persons with a history of myocardial infarction, cerebrovascular event, or acute coronary syndrome within 3 months prior to starting daprodustat. Persons with cardiac disease or cerebrovascular disease are at increased risk for arterial and venous thrombotic events. These events may be fatal and include myocardial infarction, stroke, venous thromboembolism and vascular access thrombosis. A hemoglobin increase of more than 1 g/dL over 2 weeks may contribute to the risk of development of these thrombotic events. Targeting a hemoglobin concentration greater than 11 g/dL is expected to further increase the risk of death and arterial and venous thrombotic events (as occurs with erythropoiesis stimulating agents, which also increase erythropoietin concentrations). Clinical trials have not identified a target hemoglobin concentration, daprodustat dose, or dosing strategy that does not increase the risk of thrombotic vascular events. Use the lowest dose of daprodustat that is sufficient to reduce the need for red blood cell transfusions. Adhere to dosing and hemoglobin monitoring recommendations to avoid excessive erythropoiesis. Advise persons to seek immediate medical attention if they develop signs or symptoms of myocardial infarction, stroke, venous thromboembolism, or thrombosis of vascular access; evaluate and manage promptly if these occur.
Consider any history of heart failure when deciding whether to use daprodustat. Persons with a pre-existing history of heart failure were at increased risk for hospitalization for heart failure in a clinical trial with daprodustat. Advise persons of the signs and symptoms of heart failure and to immediately report any worsening symptoms to their health care provider. A large cardiovascular outcomes trial in adults with anemia of chronic kidney disease not receiving dialysis demonstrated an increased risk of hospitalization for heart failure in daprodustat-treated subjects treated compared to recombinant human erythropoietin-treated subjects.
Daprodustat is contraindicated in persons with uncontrolled hypertension. Periodically monitor blood pressure and adjust or initiate anti-hypertensive therapy as needed during daprodustat treatment.
Persons with a history of gastrointestinal erosions, peptic ulcer disease, use of concomitant medications that increase the risk of gastrointestinal erosion, or current tobacco smoking or ethanol ingestion are at increased risk for development of gastrointestinal erosions with the use of daprodustat. Advise persons of the signs and symptoms of gastric and esophageal erosions and of gastrointestinal bleeding and to seek prompt medical care if these occur. A large cardiovascular outcomes trial in adults with anemia of chronic kidney disease not receiving dialysis demonstrated a risk of serious gastric or esophageal erosions in subjects treated with daprodustat.
Daprodustat is not recommended and has not been studied in persons with active neoplastic disease; increased hypoxia inducible factor (HIF)-1 concentrations may be associated with unfavorable effects on cancer growth.
Daprodustat use is not recommended in persons with severe hepatic disease (Child-Pugh Class C). Reduce the starting daprodustat dose in persons with moderate hepatic impairment (Child-Pugh Class B) except in persons whose starting dose is already the lowest dose. No adjustment of the starting daprodustat dose is required in persons with mild hepatic impairment (Child-Pugh Class A). Assess serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and total bilirubin prior to initiation of daprodustat. Repeat liver function tests if signs or symptoms consistent with liver disease occur during treatment with daprodustat.
Available data with use of daprodustat in human pregnancy are insufficient to establish a drug associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal studies, adverse fetal outcomes, including embryonic and fetal loss and reduced fetal weight, occurred in pregnant rats and rabbits given daprodustat during organogenesis at doses that caused maternal toxicity and polycythemia. Advise pregnant women of the potential risk to the fetus. There are risks to the mother and fetus associated with chronic kidney disease (CKD), including maternal hypertension, preeclampsia, miscarriage, stillbirth, preterm delivery, low birth weight infants, and polyhydramnios.
Given the risk for serious adverse reactions (e.g., thrombotic vascular events) observed in adults treated with daprodustat, avoid breast-feeding during treatment with daprodustat, and for 1 week after the final dose. There are no data on the presence of daprodustat in human milk, the effects on the breast-fed infant, or the effects on milk production. Daprodustat is present in the milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk.
General Dosing Information
-Correct and exclude other causes of anemia (e.g., vitamin deficiency, metabolic, or chronic inflammatory conditions, bleeding) prior to initiating treatment with daprodustat.
-Evaluate iron studies before and during treatment with daprodustat. Administer supplemental iron therapy when serum ferritin is less than 100 mcg/L or when serum transferrin saturation is less than 20%.
-Assess serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and total bilirubin prior to initiation of daprodustat. Repeat liver function tests if signs or symptoms consistent with liver disease occur during treatment with daprodustat.
For the treatment of anemia of chronic kidney disease in persons receiving dialysis for 4 months or more:
-for the treatment of anemia of chronic kidney disease in persons receiving dialysis for 4 months or more and not being treated with an erythropoiesis stimulating agent:
Oral dosage:
Adults with pre-treatment hemoglobin concentration of less than 9 mg/dL: 4 mg PO once daily, initially. Monitor hemoglobin every 2 weeks for the first month and then every 4 weeks thereafter (after initiation of therapy and each dose adjustment), and adjust dose based on hemoglobin (rate of hemoglobin rise and decline as well as hemoglobin variability) no more frequently than every 4 weeks. Max: 24 mg/day. Do not continue treatment with daprodustat beyond 24 weeks of therapy if a clinically significant increase in hemoglobin concentration is not achieved; consider alternative explanations for an inadequate response and treat before restarting therapy. Coadministration of certain drugs may need to be avoided or dosage adjustment may be necessary; review drug interactions.
Adults with pre-treatment hemoglobin concentration of 9 to 10 mg/dL: 2 mg PO once daily, initially. Monitor hemoglobin every 2 weeks for the first month and then every 4 weeks thereafter (after initiation of therapy and each dose adjustment), and adjust dose based on hemoglobin (rate of hemoglobin rise and decline as well as hemoglobin variability) no more frequently than every 4 weeks. Max: 24 mg/day. Do not continue treatment with daprodustat beyond 24 weeks of therapy if a clinically significant increase in hemoglobin concentration is not achieved; consider alternative explanations for an inadequate response and treat before restarting therapy. Coadministration of certain drugs may need to be avoided or dosage adjustment may be necessary; review drug interactions.
Adults with pre-treatment hemoglobin concentration of more than 10 mg/dL: 1 mg PO once daily, initially. Monitor hemoglobin every 2 weeks for the first month and then every 4 weeks thereafter (after initiation of therapy and each dose adjustment), and adjust dose based on hemoglobin (rate of hemoglobin rise and decline as well as hemoglobin variability) no more frequently than every 4 weeks. Max: 24 mg/day. Do not continue treatment with daprodustat beyond 24 weeks of therapy if a clinically significant increase in hemoglobin concentration is not achieved; consider alternative explanations for an inadequate response and treat before restarting therapy. Coadministration of certain drugs may need to be avoided or dosage adjustment may be necessary; review drug interactions.
-for the treatment of anemia of chronic kidney disease in persons receiving dialysis for 4 months or more and being transitioned from an erythropoiesis stimulating agent:
Oral dosage:
Adults transitioning from epoetin alpha 2,000 units/week or less IV, darbepoetin alfa 20 to 30 mcg/4 weeks IV/subcutaneously, or methoxy PEG-epoetin beta 30 to 40 mcg/month IV/subcutaneously: 4 mg PO once daily, initially. Monitor hemoglobin every 2 weeks for the first month and then every 4 weeks thereafter (after initiation of therapy and each dose adjustment), and adjust dose based on hemoglobin (rate of hemoglobin rise and decline as well as hemoglobin variability) no more frequently than every 4 weeks. Max: 24 mg/day. Do not continue treatment with daprodustat beyond 24 weeks of therapy if a clinically significant increase in hemoglobin concentration is not achieved; consider alternative explanations for an inadequate response and treat before restarting therapy. For persons on subcutaneous epoetin alpha, convert the epoetin alpha subcutaneous dose to an equivalent weekly intravenous dose by multiplying the weekly subcutaneous dose by 1.42. Coadministration of certain drugs may need to be avoided or dosage adjustment may be necessary; review drug interactions.
Adults transitioning from epoetin alpha 2,001 to 9,999 units/week IV, darbepoetin alfa 31 to 150 mcg/4 weeks IV/subcutaneously, or methoxy PEG-epoetin beta 41 to 180 mcg/month IV/subcutaneously: 6 mg PO once daily, initially. Monitor hemoglobin every 2 weeks for the first month and then every 4 weeks thereafter (after initiation of therapy and each dose adjustment), and adjust dose based on hemoglobin (rate of hemoglobin rise and decline as well as hemoglobin variability) no more frequently than every 4 weeks. Max: 24 mg/day. Do not continue treatment with daprodustat beyond 24 weeks of therapy if a clinically significant increase in hemoglobin concentration is not achieved; consider alternative explanations for an inadequate response and treat before restarting therapy. For persons on subcutaneous epoetin alpha, convert the epoetin alpha subcutaneous dose to an equivalent weekly intravenous dose by multiplying the weekly subcutaneous dose by 1.42. Coadministration of certain drugs may need to be avoided or dosage adjustment may be necessary; review drug interactions.
Adults transitioning from epoetin alpha 10,000 to 19,999 units/week IV, darbepoetin alfa 151 to 300 mcg/4 weeks IV/subcutaneously, or methoxy PEG-epoetin beta 181 to 360 mcg/month IV/subcutaneously: 8 mg PO once daily, initially. Monitor hemoglobin every 2 weeks for the first month and then every 4 weeks thereafter (after initiation of therapy and each dose adjustment), and adjust dose based on hemoglobin (rate of hemoglobin rise and decline as well as hemoglobin variability) no more frequently than every 4 weeks. Max: 24 mg/day. Do not continue treatment with daprodustat beyond 24 weeks of therapy if a clinically significant increase in hemoglobin concentration is not achieved; consider alternative explanations for an inadequate response and treat before restarting therapy. For persons on subcutaneous epoetin alpha, convert the epoetin alpha subcutaneous dose to an equivalent weekly intravenous dose by multiplying the weekly subcutaneous dose by 1.42. Coadministration of certain drugs may need to be avoided or dosage adjustment may be necessary; review drug interactions.
Adults transitioning from epoetin alpha 20,000 units/week or more IV, darbepoetin alfa more than 300 mcg/4 weeks IV/subcutaneously, or methoxy PEG-epoetin beta more than 360 mcg/month IV/subcutaneously: 12 mg PO once daily, initially. Monitor hemoglobin every 2 weeks for the first month and then every 4 weeks thereafter (after initiation of therapy and each dose adjustment), and adjust dose based on hemoglobin (rate of hemoglobin rise and decline as well as hemoglobin variability) no more frequently than every 4 weeks. Max: 24 mg/day. Do not continue treatment with daprodustat beyond 24 weeks of therapy if a clinically significant increase in hemoglobin concentration is not achieved; consider alternative explanations for an inadequate response and treat before restarting therapy. For persons on subcutaneous epoetin alpha, convert the epoetin alpha subcutaneous dose to an equivalent weekly intravenous dose by multiplying the weekly subcutaneous dose by 1.42. Coadministration of certain drugs may need to be avoided or dosage adjustment may be necessary; review drug interactions.
Therapeutic Drug Monitoring:
Dosage Adjustment Based on Hemoglobin
-Do not target a hemoglobin more than 11 g/dL.
-Monitor hemoglobin every 2 weeks for the first month and then every 4 weeks thereafter (after initiation of therapy and each dose adjustment), and adjust dose based on hemoglobin (rate of hemoglobin rise and decline as well as hemoglobin variability) no more frequently than every 4 weeks.
-If the dose needs to be adjusted, increase or decrease by 1 dose level at a time (i.e., 1 mg, 2 mg, 4 mg, 6 mg, 12 mg, 16 mg, or 24 mg).
-Decrease the dose if hemoglobin increases rapidly (e.g., more than 1 g/dL over 2 weeks or more than 2 g/dL over 4 weeks) or if the hemoglobin exceeds 11 g/dL.
-If the hemoglobin exceeds 12 g/dL, interrupt treatment with daprodustat. When the hemoglobin is within the target range, treatment may be restarted at 1 dose level lower.
Maximum Dosage Limits:
-Adults
24 mg/day PO.
-Geriatric
24 mg/day PO.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Reduce the starting dose of daprodustat by one-half in persons with moderate hepatic impairment (Child-Pugh Class B) except in persons whose starting dose is already 1 mg. Daprodustat use in persons with severe hepatic impairment (Child-Pugh Class C) is not recommended.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Carbamazepine: (Moderate) Monitor for a decrease in daprodustat efficacy during concomitant use of daprodustat and carbamazepine. Concomitant use may decrease daprodustat exposure. Daprodustat is a CYP2C8 substrate and carbamazepine is a CYP2C8 inducer.
Clopidogrel: (Major) Reduce the initial daprodustat dose by half during concomitant use of clopidogrel unless the daprodustat dose is already 1 mg. Monitor hemoglobin and further adjust the daprodustat dose as appropriate. Concomitant use may increase daprodustat exposure and the risk for daprodustat-related adverse reactions. Daprodustat is a CYP2C8 substrate and clopidogrel is a moderate CYP2C8 inhibitor. Concomitant use with a moderate CYP2C8 inhibitor is expected to increase daprodustat overall exposure by approximately 4-fold.
Deferasirox: (Major) Reduce the initial daprodustat dose by half during concomitant use of deferasirox unless the daprodustat dose is already 1 mg. Monitor hemoglobin and further adjust the daprodustat dose as appropriate. Concomitant use may increase daprodustat exposure and the risk for daprodustat-related adverse reactions. Daprodustat is a CYP2C8 substrate and deferasirox is a moderate CYP2C8 inhibitor. Concomitant use with a moderate CYP2C8 inhibitor is expected to increase daprodustat overall exposure by approximately 4-fold.
Gemfibrozil: (Contraindicated) Concurrent use of daprodustat and gemfibrozil is contraindicated due the risk of increased daprodustat exposure which may increase the risk of daprodustat-related adverse reactions. Daprodustat is a CYP2C8 substrate and gemfibrozil is a strong CYP2C8 inhibitor. Concomitant use increased daprodustat exposure by 18.6-fold.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Monitor for a decrease in daprodustat efficacy during concomitant use of daprodustat and rifampin. Concomitant use may decrease daprodustat exposure. Daprodustat is a CYP2C8 substrate and rifampin is a CYP2C8 inducer.
Isoniazid, INH; Rifampin: (Moderate) Monitor for a decrease in daprodustat efficacy during concomitant use of daprodustat and rifampin. Concomitant use may decrease daprodustat exposure. Daprodustat is a CYP2C8 substrate and rifampin is a CYP2C8 inducer.
Leflunomide: (Major) Reduce the initial daprodustat dose by half during concomitant use of leflunomide unless the daprodustat dose is already 1 mg. Monitor hemoglobin and further adjust the daprodustat dose as appropriate. Concomitant use may increase daprodustat exposure and the risk for daprodustat-related adverse reactions. Daprodustat is a CYP2C8 substrate and leflunomide is a moderate CYP2C8 inhibitor. Concomitant use with a moderate CYP2C8 inhibitor is expected to increase daprodustat overall exposure by approximately 4-fold.
Meropenem: (Moderate) Monitor for a decrease in daprodustat efficacy during concomitant use of daprodustat and meropenem. Concomitant use may decrease daprodustat exposure. Daprodustat is a CYP2C8 substrate and meropenem is a CYP2C8 inducer.
Meropenem; Vaborbactam: (Moderate) Monitor for a decrease in daprodustat efficacy during concomitant use of daprodustat and meropenem. Concomitant use may decrease daprodustat exposure. Daprodustat is a CYP2C8 substrate and meropenem is a CYP2C8 inducer.
Mifepristone: (Major) Reduce the initial daprodustat dose by half during concomitant use of mifepristone unless the daprodustat dose is already 1 mg. Monitor hemoglobin and further adjust the daprodustat dose as appropriate. Concomitant use may increase daprodustat exposure and the risk for daprodustat-related adverse reactions. Daprodustat is a CYP2C8 substrate and mifepristone is a moderate CYP2C8 inhibitor. Concomitant use with a moderate CYP2C8 inhibitor is expected to increase daprodustat overall exposure by approximately 4-fold.
Omaveloxolone: (Moderate) Monitor for a decrease in daprodustat efficacy during concomitant use of daprodustat and omaveloxolone. Concomitant use may decrease daprodustat exposure. Daprodustat is a CYP2C8 substrate and omaveloxolone is a CYP2C8 inducer.
Pirtobrutinib: (Major) Reduce the initial daprodustat dose by half during concomitant use of pirtobrutinib unless the daprodustat dose is already 1 mg. Monitor hemoglobin and further adjust the daprodustat dose as appropriate. Concomitant use may increase daprodustat exposure and the risk for daprodustat-related adverse reactions. Daprodustat is a CYP2C8 substrate and pirtobrutinib is a moderate CYP2C8 inhibitor. Concomitant use with a moderate CYP2C8 inhibitor is expected to increase daprodustat overall exposure by approximately 4-fold.
Rifampin: (Moderate) Monitor for a decrease in daprodustat efficacy during concomitant use of daprodustat and rifampin. Concomitant use may decrease daprodustat exposure. Daprodustat is a CYP2C8 substrate and rifampin is a CYP2C8 inducer.
Rifapentine: (Moderate) Monitor for a decrease in daprodustat efficacy during concomitant use of daprodustat and rifapentine. Concomitant use may decrease daprodustat exposure. Daprodustat is a CYP2C8 substrate and rifapentine is a CYP2C8 inducer.
Selpercatinib: (Major) Reduce the initial daprodustat dose by half during concomitant use of selpercatinib unless the daprodustat dose is already 1 mg. Monitor hemoglobin and further adjust the daprodustat dose as appropriate. Concomitant use may increase daprodustat exposure and the risk for daprodustat-related adverse reactions. Daprodustat is a CYP2C8 substrate and selpercatinib is a moderate CYP2C8 inhibitor. Concomitant use with a moderate CYP2C8 inhibitor is expected to increase daprodustat overall exposure by approximately 4-fold.
Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Major) Reduce the initial daprodustat dose by half during concomitant use of sulfamethoxazole unless the daprodustat dose is already 1 mg. Monitor hemoglobin and further adjust the daprodustat dose as appropriate. Concomitant use may increase daprodustat exposure and the risk for daprodustat-related adverse reactions. Daprodustat is a CYP2C8 substrate and sulfamethoxazole is a moderate CYP2C8 inhibitor. Concomitant use with a moderate CYP2C8 inhibitor is expected to increase daprodustat overall exposure by approximately 4-fold.
Teriflunomide: (Major) Reduce the initial daprodustat dose by half during concomitant use of teriflunomide unless the daprodustat dose is already 1 mg. Monitor hemoglobin and further adjust the daprodustat dose as appropriate. Concomitant use may increase daprodustat exposure and the risk for daprodustat-related adverse reactions. Daprodustat is a CYP2C8 substrate and teriflunomide is a moderate CYP2C8 inhibitor. Concomitant use with a moderate CYP2C8 inhibitor is expected to increase daprodustat overall exposure by approximately 4-fold.
Daprodustat is a reversible inhibitor of hypoxia-inducible factor (HIF), prolyl 4-hydroxylases (PH)1, PH2, and PH3. This activity results in the stabilization and nuclear accumulation of HIF-1-alpha and HIF-2-alpha transcription factors, leading to increased transcription of the HIF-responsive genes, including erythropoietin. Daprodustat increased serum transferrin and total iron binding capacity (TIBC) and decreased serum ferritin, transferrin saturation, and hepcidin when administered for 52 weeks in adults with anemia of chronic kidney disease on dialysis.
Daprodustat is administered orally. Plasma protein binding of daprodustat is more than 99% in vitro and the Vd at steady-state after intravenous dosing is 14.3 L. The distribution of daprodustat is similar between plasma and blood cells (blood:plasma ratio of 1.23). Daprodustat is metabolized by hepatic cytochrome P450 (CYP) enzymes, primarily by CYP2C8 (95%) with a minor contribution by CYP3A4 (5%). Three daprodustat metabolites have been identified with each accounting for more than 10% of circulating drug-related material. In-vitro and non-clinical data suggest that each metabolite may contribute to the pharmacologic response in vivo; however, the extent of this contribution is unknown. The mean clearance of daprodustat from plasma is 18.9 L/hour. Within 7 days of an oral dose of radiolabeled daprodustat, 74% of the radioactivity is recovered in the feces and 21% in the urine. Approximately 99.5% of the daprodustat dose is excreted as oxidative metabolites. The terminal elimination half-life of daprodustat is approximately 1 to 4 hours.
Affected cytochrome P450 isoenzymes and drug transporters: CYP2C8, CYP3A4, BCRP, OAT1, OAT3
Daprodustat is predominantly metabolized by CYP2C8; CYP3A4 is also involved to a lesser degree. Some oxidative metabolites of daprodustat are substrates of Organic Anion Transporter (OAT)1 or OAT3; however, the clinical significance of this is unknown. Daprodustat is also a substrate of Breast Cancer Resistance Protein (BCRP); however, the risk of significant drug interactions between daprodustat and BCRP inhibitors is considered low based on daprodustat's absorption and metabolism profile.
-Route-Specific Pharmacokinetics
Oral Route
Daprodustat is readily absorbed after oral administration with a median Tmax of 1 to 4 hours. The absolute bioavailability of daprodustat is 65%. Administration of daprodustat with a high fat/high calorie meal does not significantly alter daprodustat exposure compared to administration without food. Daprodustat displays a dose-dependent increase in endogenous erythropoietin within 6 to 8 hours after administration. Peak increases in reticulocyte counts occur between 7 and 15 days after repeat dosing, with subsequent increases in red blood cell production. New hemoglobin steady-state concentrations are reached several weeks after initial daprodustat administration (approximately 4 weeks in erythropoiesis-stimulating agent (ESA) users and approximately 16 to 20 weeks in ESA-non-users).
-Special Populations
Hepatic Impairment
After administration of a single daprodustat 6 mg dose, the daprodustat mean Cmax and AUC increased by 2-fold and unbound exposure increased by 2.3-fold in subjects with moderate hepatic impairment (Child-Pugh Class B) compared to subjects with normal hepatic and renal function. In subjects with mild hepatic impairment (Child-Pugh Class A), the daprodustat mean Cmax was similar while AUC increased by 1.5-fold and unbound Cmax and AUC increased by 1.6 and 2.2-fold, respectively, compared to subjects with normal hepatic and renal function. The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of daprodustat has not been studied and is unknown.
Renal Impairment
Daprodustat steady-state exposure is similar in subjects with normal renal function and varying degrees of renal impairment. Additionally, daprodustat exposure is not significantly affected by hemodialysis or peritoneal dialysis. The systemic exposure of daprodustat metabolites was higher in Stage 3 to 5 chronic kidney disease (CKD) compared to subjects with normal renal function. Exposures of metabolites were higher on non-dialysis days compared to dialysis days.
Geriatric
Population pharmacokinetic analyses in adults with chronic kidney disease (CKD) (age 22 years to 93 years) demonstrated that age did not influence the pharmacokinetics of daprodustat.