Peringatan Keamanan

Headache and gastrointestinal adverse reactions (e.g., nausea) may be seen with acute overdose with daprodustat. There is no specific antidote. Hemodialysis will not substantially remove daprodustat because it is highly protein bound.L44958

Daprodustat

DB11682

small molecule approved investigational

Deskripsi

Daprodustat is a small-molecule hypoxia-inducible factor (HIF) prolyl hydroxylase (PHD) inhibitor that was developed by GSK.A254167,A254162 Patients with CKD cannot induce erythropoietin (EPO) production in response to hypoxia or anemia. As a potent inhibitor of PHD1, PHD2 and PHD3 (??1000-fold selectivity), daprodustat stabilizes cellular HIF1? and HIF2? and the induces erythropoiesis.A254157 A phase 3 clinical trial (NCT02879305) found that in patients with CKD undergoing dialysis, daprodustat was non-inferior to erythropoiesis-stimulating agents regarding the change in the hemoglobin level from baseline and cardiovascular outcomes.A254172

In June 2020, daprodustat was first approved in Japan for the treatment of renal anemia.A254157 On October 2022, the FDA Cardiovascular and Renal Drugs Advisory Committee (CRDAC) supported that the benefit of treatment with daprodustat outweighs the risks for adult dialysis patients with anemia of CKD but not for non-dialysis patients with anemia of CKD.L43857 On February 1, 2023, daprodustat was fully approved by the FDA as the first oral treatment for anemia caused by chronic kidney disease in patients on dialysis.L44963 The drug is currently under EMA review.

Struktur Molekul 2D

Berat 393.44
Wujud solid

Peta Jejaring Molekuler
Legenda: Obat • Target • Gen • Enzim • (Panah → menunjukkan arah efek / relasi) • Transporter • Carrier

Profil Farmakokinetik

Waktu Paruh (Half-Life) The terminal elimination half-life of daprodustat ranges from one to four hours.[L44958]
Volume Distribusi Daprodustat has an approximately equal distribution between plasma and blood cells (blood:plasma ratio of 1.23). Following intravenous dosing, the volume of distribution at steady-state in healthy subjects is 14.3 L.[L44958]
Klirens (Clearance) Mean clearance from plasma was 18.9 L/h, which correlates to blood clearance of 15 L/h and equates to a hepatic extraction of approximately 18%.[L44958]

Absorpsi

Daprodustat exposure generally increases in a dose-proportional manner over the range of therapeutic doses. Steady-state concentrations are achieved within 24 hours of dosing. Following oral administration, daprodustat is readily absorbed with a median time to peak concentration (Tmax) in healthy subjects ranging from one to four hours. The absolute bioavailability of daprodustat is 65%. Administration of daprodustat with a high-fat or high-calorie meal did not significantly alter daprodustat exposure compared to administration in the fasted state.L44958

Metabolisme

In vitro, daprodustat is primarily metabolized by CYP2C8 (95% contribution), with a minor contribution by CYP3A4 (5%). Following oral or intravenous administration of radiolabeled daprodustat to healthy adults, approximately 40% of the total circulating radioactivity in plasma was daprodustat, and the remaining 60% was metabolites.L44958 The parent drug is the principal circulating component in plasma.L44958 Of the six metabolites of daprodustat that were characterized, the major metabolites were M2 (GSK2391220), M3 (GSK2506104), and M13 (GSK2531401), with each metabolite accounting for more than 10% of circulating radioactivity in plasma.A256943 In humans, each metabolite circulates primarily as a single stereoisomeric form.A256953 In vitro and non-clinical studies suggest that these identified metabolites have a comparable pharmacological activity to the parent drug; however, the extent of the pharmacological contribution of each metabolite is unknown.A256943,L44958

Rute Eliminasi

Within seven days of an oral dose of radiolabeled daprodustat, 74% of the radioactivity was recovered in the feces, and 21% of the radioactivity was recovered in the urine. Approximately 99.5% of the dose was excreted as oxidative metabolites, with the remaining fraction representing the unchanged parent drug.L44958

Interaksi Makanan

1 Data
  • 1. Take with or without food. Food does not affect drug absorption or exposure. Daprodustat can be taken without regard to concomitant administration of iron or phosphate binders, and it can be administered without regard to the timing or type of dialysis.

Interaksi Obat

225 Data
Mifepristone The serum concentration of Daprodustat can be increased when it is combined with Mifepristone.
Phenytoin The metabolism of Daprodustat can be increased when combined with Phenytoin.
Secobarbital The metabolism of Daprodustat can be increased when combined with Secobarbital.
Rifampin The metabolism of Daprodustat can be increased when combined with Rifampicin.
Troglitazone The metabolism of Daprodustat can be decreased when combined with Troglitazone.
Bexarotene The metabolism of Daprodustat can be decreased when combined with Bexarotene.
Diltiazem The metabolism of Daprodustat can be decreased when combined with Diltiazem.
Trimethoprim The metabolism of Daprodustat can be decreased when combined with Trimethoprim.
Levothyroxine The metabolism of Daprodustat can be decreased when combined with Levothyroxine.
Loratadine The metabolism of Daprodustat can be decreased when combined with Loratadine.
Quinine The metabolism of Daprodustat can be decreased when combined with Quinine.
Ritonavir The metabolism of Daprodustat can be decreased when combined with Ritonavir.
Medroxyprogesterone acetate The metabolism of Daprodustat can be decreased when combined with Medroxyprogesterone acetate.
Nicardipine The metabolism of Daprodustat can be decreased when combined with Nicardipine.
Efavirenz The metabolism of Daprodustat can be decreased when combined with Efavirenz.
Tamoxifen The metabolism of Daprodustat can be decreased when combined with Tamoxifen.
Ketoconazole The metabolism of Daprodustat can be decreased when combined with Ketoconazole.
Irbesartan The metabolism of Daprodustat can be decreased when combined with Irbesartan.
Oxybutynin The metabolism of Daprodustat can be decreased when combined with Oxybutynin.
Fluvastatin The metabolism of Daprodustat can be decreased when combined with Fluvastatin.
Pioglitazone The metabolism of Daprodustat can be decreased when combined with Pioglitazone.
Saquinavir The metabolism of Daprodustat can be decreased when combined with Saquinavir.
Genistein The metabolism of Daprodustat can be decreased when combined with Genistein.
Topiroxostat The metabolism of Daprodustat can be decreased when combined with Topiroxostat.
Abiraterone The metabolism of Daprodustat can be decreased when combined with Abiraterone.
Eltrombopag The metabolism of Daprodustat can be decreased when combined with Eltrombopag.
Teriflunomide The metabolism of Daprodustat can be decreased when combined with Teriflunomide.
Enzalutamide The metabolism of Daprodustat can be decreased when combined with Enzalutamide.
Pirtobrutinib The metabolism of Daprodustat can be decreased when combined with Pirtobrutinib.
Erlotinib The metabolism of Daprodustat can be decreased when combined with Erlotinib.
Fluticasone propionate The metabolism of Daprodustat can be decreased when combined with Fluticasone propionate.
Clopidogrel The metabolism of Daprodustat can be decreased when combined with Clopidogrel.
Candesartan cilexetil The metabolism of Daprodustat can be decreased when combined with Candesartan cilexetil.
Salmeterol The metabolism of Daprodustat can be decreased when combined with Salmeterol.
Felodipine The metabolism of Daprodustat can be decreased when combined with Felodipine.
Gemfibrozil The metabolism of Daprodustat can be decreased when combined with Gemfibrozil.
Dabrafenib The metabolism of Daprodustat can be decreased when combined with Dabrafenib.
Fluticasone The metabolism of Daprodustat can be decreased when combined with Fluticasone.
Mometasone furoate The metabolism of Daprodustat can be decreased when combined with Mometasone furoate.
Pyrimethamine The metabolism of Daprodustat can be decreased when combined with Pyrimethamine.
Ticlopidine The metabolism of Daprodustat can be decreased when combined with Ticlopidine.
Cimetidine The metabolism of Daprodustat can be decreased when combined with Cimetidine.
Rofecoxib The metabolism of Daprodustat can be decreased when combined with Rofecoxib.
Terbinafine The metabolism of Daprodustat can be decreased when combined with Terbinafine.
Quinidine The metabolism of Daprodustat can be decreased when combined with Quinidine.
Ketoprofen The metabolism of Daprodustat can be decreased when combined with Ketoprofen.
Fenofibrate The metabolism of Daprodustat can be decreased when combined with Fenofibrate.
Atazanavir The metabolism of Daprodustat can be decreased when combined with Atazanavir.
Tegaserod The metabolism of Daprodustat can be decreased when combined with Tegaserod.
Bezafibrate The metabolism of Daprodustat can be decreased when combined with Bezafibrate.
Pazopanib The metabolism of Pazopanib can be decreased when combined with Daprodustat.
Cabozantinib The metabolism of Daprodustat can be decreased when combined with Cabozantinib.
Candesartan The metabolism of Daprodustat can be decreased when combined with Candesartan.
Diethylstilbestrol The metabolism of Daprodustat can be decreased when combined with Diethylstilbestrol.
Terfenadine The metabolism of Daprodustat can be decreased when combined with Terfenadine.
Cerivastatin The metabolism of Daprodustat can be decreased when combined with Cerivastatin.
Raloxifene The metabolism of Daprodustat can be decreased when combined with Raloxifene.
Simvastatin The metabolism of Daprodustat can be decreased when combined with Simvastatin.
Nilutamide The metabolism of Daprodustat can be decreased when combined with Nilutamide.
Mometasone The metabolism of Daprodustat can be decreased when combined with Mometasone.
Metronidazole The metabolism of Daprodustat can be decreased when combined with Metronidazole.
Ethinylestradiol The metabolism of Daprodustat can be decreased when combined with Ethinylestradiol.
Miconazole The metabolism of Daprodustat can be decreased when combined with Miconazole.
Deferasirox The metabolism of Daprodustat can be decreased when combined with Deferasirox.
Quercetin The metabolism of Daprodustat can be decreased when combined with Quercetin.
Licofelone The metabolism of Daprodustat can be decreased when combined with Licofelone.
Levoketoconazole The metabolism of Daprodustat can be decreased when combined with Levoketoconazole.
Nilvadipine The metabolism of Daprodustat can be decreased when combined with Nilvadipine.
Sulfaphenazole The metabolism of Daprodustat can be decreased when combined with Sulfaphenazole.
Rilpivirine The metabolism of Daprodustat can be decreased when combined with Rilpivirine.
Vemurafenib The metabolism of Daprodustat can be decreased when combined with Vemurafenib.
Cannabidiol The metabolism of Daprodustat can be decreased when combined with Cannabidiol.
Stiripentol The metabolism of Daprodustat can be decreased when combined with Stiripentol.
Lobeglitazone The metabolism of Daprodustat can be decreased when combined with Lobeglitazone.
Netoglitazone The metabolism of Daprodustat can be decreased when combined with Netoglitazone.
Rivoglitazone The metabolism of Daprodustat can be decreased when combined with Rivoglitazone.
Ciglitazone The metabolism of Daprodustat can be decreased when combined with Ciglitazone.
Methylene blue The metabolism of Daprodustat can be decreased when combined with Methylene blue.
Lumacaftor The metabolism of Daprodustat can be decreased when combined with Lumacaftor.
Isavuconazole The metabolism of Daprodustat can be decreased when combined with Isavuconazole.
Alpelisib The metabolism of Daprodustat can be decreased when combined with Alpelisib.
Letermovir The metabolism of Daprodustat can be decreased when combined with Letermovir.
Triclabendazole The metabolism of Daprodustat can be decreased when combined with Triclabendazole.
Favipiravir The metabolism of Daprodustat can be decreased when combined with Favipiravir.
Balaglitazone The metabolism of Daprodustat can be decreased when combined with Balaglitazone.
Enasidenib The metabolism of Enasidenib can be decreased when combined with Daprodustat.
Selpercatinib The serum concentration of Daprodustat can be increased when it is combined with Selpercatinib.
Pralsetinib The metabolism of Daprodustat can be decreased when combined with Pralsetinib.
Linzagolix The serum concentration of Daprodustat can be increased when it is combined with Linzagolix.
Rifabutin The metabolism of Daprodustat can be increased when combined with Rifabutin.
Tecovirimat The metabolism of Daprodustat can be increased when combined with Tecovirimat.
Betamethasone The metabolism of Daprodustat can be increased when combined with Betamethasone.
Cyclophosphamide The metabolism of Daprodustat can be increased when combined with Cyclophosphamide.
Hydrocortisone The metabolism of Daprodustat can be increased when combined with Hydrocortisone.
Probenecid The metabolism of Daprodustat can be increased when combined with Probenecid.
Ifosfamide The metabolism of Daprodustat can be increased when combined with Ifosfamide.
Rifapentine The metabolism of Daprodustat can be increased when combined with Rifapentine.
Dexamethasone The metabolism of Daprodustat can be increased when combined with Dexamethasone.
Cenobamate The metabolism of Daprodustat can be increased when combined with Cenobamate.
Prednisolone phosphate The metabolism of Daprodustat can be increased when combined with Prednisolone phosphate.

Target Protein

Egl nine homolog 1 EGLN1
Prolyl hydroxylase EGLN2 EGLN2
Prolyl hydroxylase EGLN3 EGLN3

Referensi & Sumber

Artikel (PubMed)
  • PMID: 32880805
    Dhillon S: Daprodustat: First Approval. Drugs. 2020 Sep;80(14):1491-1497. doi: 10.1007/s40265-020-01384-y.
  • PMID: 33597868
    Zheng Q, Wang Y, Yang H, Sun L, Fu X, Wei R, Liu YN, Liu WJ: Efficacy and Safety of Daprodustat for Anemia Therapy in Chronic Kidney Disease Patients: A Systematic Review and Meta-Analysis. Front Pharmacol. 2021 Jan 12;11:573645. doi: 10.3389/fphar.2020.573645. eCollection 2020.
  • PMID: 29285707
    Becker KA, Jones JJ: An Emerging Treatment Alternative for Anemia in Chronic Kidney Disease Patients: A Review of Daprodustat. Adv Ther. 2018 Jan;35(1):5-11. doi: 10.1007/s12325-017-0655-z. Epub 2017 Dec 28.
  • PMID: 34739194
    Singh AK, Carroll K, Perkovic V, Solomon S, Jha V, Johansen KL, Lopes RD, Macdougall IC, Obrador GT, Waikar SS, Wanner C, Wheeler DC, Wiecek A, Blackorby A, Cizman B, Cobitz AR, Davies R, Dole J, Kler L, Meadowcroft AM, Zhu X, McMurray JJV: Daprodustat for the Treatment of Anemia in Patients Undergoing Dialysis. N Engl J Med. 2021 Dec 16;385(25):2325-2335. doi: 10.1056/NEJMoa2113379. Epub 2021 Nov 5.
  • PMID: 34713596
    Mahar KM, Caltabiano S, Andrews S, Ramanjineyulu B, Chen L, Young G, Pereira A, Lindsay AC, van den Berg F, Cobitz AR: Clinical Pharmacokinetics of Daprodustat: Results of an Absorption, Distribution, and Excretion Study With Intravenous Microtracer and Concomitant Oral Doses for Bioavailability Determination. Clin Pharmacol Drug Dev. 2021 Dec;10(12):1419-1431. doi: 10.1002/cpdd.1029. Epub 2021 Oct 28.
  • PMID: 26688343
    Licea Perez H, Knecht D, Evans CA: Overcoming bioanalytical challenges associated with the separation and quantitation of GSK1278863, a HIF-prolyl hydroxylase inhibitor, and its 14 stereoisomeric metabolites. J Chromatogr B Analyt Technol Biomed Life Sci. 2016 Jan 15;1009-1010:7-16. doi: 10.1016/j.jchromb.2015.11.057. Epub 2015 Dec 4.

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