Peringatan Keamanan

LD50 information for darolutamide is not readily available in the literature.

To this date, there is no known antidote in existence for an overdose with darolutamide. The highest dose clinically documented was a twice daily dose of 900 mg, totalling 1800 mg. Dose-limiting toxicities have not been observed with this drug. In patients with healthy kidney and liver function, a high dose of darolutamide will likely not lead to systemic toxicity.L10872 If a high dose (higher than recommended on labeling) is ingested in a patient with renal or hepatic impairment, and toxic symptoms occur, pause treatment with darolutamide and offer supportive treatment until symptoms resolve.L10872

Darolutamide

DB12941

small molecule approved investigational

Deskripsi

Darolutamide is a nonsteroidal androgen receptor antagonist for the treatment of castrate-resistant, non-metastatic prostate cancer (nmCRPC). This condition occurs in the majority of patients with advanced prostate cancer who have been treated with androgen receptor antagonists.A189063 Though prior treatment for prostate cancer has been successful for these patients, the cancer eventually progresses to become resistant to existing therapies. This warrants further treatment.

The goal of treatment with darolutamide is to delay the progression of prostate cancer to metastatic disease, increasing quality of life and life expectancy for those with advanced prostate cancer.A189054,A189063 Darolutamide was developed by Bayer HealthCare Pharmaceuticals Inc. and approved by the FDA on July 30th, 2019.L10887

Struktur Molekul 2D

Berat 398.85
Wujud solid

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

Profil Farmakokinetik

Waktu Paruh (Half-Life) The half-life of darolutamide and its active metabolite, keto-darolutamide is about 20 hours.[L10872] A phase 1 study determined a terminal half life ranging between 10-15 hours.[A189054]
Volume Distribusi After intravenous administration, the apparent volume of distribution of darolutamide is about 119L.[L10872]
Klirens (Clearance) The clearance of darolutamide after an intravenous dose is 116 mL/min (39.7%).[L10872]

Absorpsi

Darolutamide is absorbed in the gastrointestinal tract.L10872 In the fasted state, peak concentrations are reached within 3-5 hours, and within 3-8 hours in the fed state. Median Tmax is between 3-6 hours.A189054The average darolutamide steady-state peak plasma concentration after a 600 mg twice daily dose is approximately 4.79 mg/L. The Cmax is attained approximately 4 hours after administration of a single 600 mg oral dose. The AUC 0-12h is approximately 52.82 h•?g/mL.L10872 Effects of food The absolute bioavailability of darolutamide is approximately 30% after fasting and taking a single 300 mg dose. Steady-state concentrations are attained between 2 and 5 days after repeated administration with food. The bioavailability of darolutamide increases by 2.0 to 2.5 times when it is given with food.A189063,L10872,L10890

Metabolisme

Darolutamide is mainly metabolized by the CYP3A4 hepatic microsomal enzymeA189051 in addition to UGT1A9 and UGT1A1. The main active metabolite keto-darolutamide in found in the plasma at 2 times the concentration of darolutamide.L10872

Rute Eliminasi

In a pharmacokinetic study, a radiolabeled dose of darolutamide in an oral solution showed that 63.4% of darolutamide-related material was excreted in the urine (7% of which was unchanged drug) and 32.4% in the feces (with 30% unchanged drug).L10872

Interaksi Makanan

2 Data
  • 1. Avoid St. John's Wort. This herb induces CYP3A and P glycoprotein and may reduce the serum concentration of darolutamide.
  • 2. Take with food. This increases the bioavailability of darolutamide.

Interaksi Obat

501 Data
Ranolazine The serum concentration of Darolutamide can be increased when it is combined with Ranolazine.
Desogestrel The metabolism of Darolutamide can be increased when combined with Desogestrel.
Lamotrigine The metabolism of Darolutamide can be increased when combined with Lamotrigine.
Ethinylestradiol The metabolism of Darolutamide can be increased when combined with Ethinylestradiol.
Testosterone propionate The metabolism of Darolutamide can be increased when combined with Testosterone propionate.
Eluxadoline The serum concentration of Eluxadoline can be increased when it is combined with Darolutamide.
Choline C 11 Darolutamide may decrease effectiveness of Choline C 11 as a diagnostic agent.
Capromab pendetide Darolutamide may decrease effectiveness of Capromab pendetide as a diagnostic agent.
Vemurafenib The serum concentration of Darolutamide can be increased when it is combined with Vemurafenib.
Apalutamide The serum concentration of Darolutamide can be decreased when it is combined with Apalutamide.
Pitolisant The serum concentration of Darolutamide can be decreased when it is combined with Pitolisant.
Isavuconazole The serum concentration of Darolutamide can be increased when it is combined with Isavuconazole.
Isavuconazonium The serum concentration of Darolutamide can be increased when it is combined with Isavuconazonium.
Cyclosporine The metabolism of Darolutamide can be decreased when combined with Cyclosporine.
Caffeine Caffeine may decrease the excretion rate of Darolutamide which could result in a higher serum level.
Pantoprazole Pantoprazole may decrease the excretion rate of Darolutamide which could result in a higher serum level.
Diethylstilbestrol Diethylstilbestrol may decrease the excretion rate of Darolutamide which could result in a higher serum level.
Beclomethasone dipropionate Beclomethasone dipropionate may decrease the excretion rate of Darolutamide which could result in a higher serum level.
Progesterone Progesterone may decrease the excretion rate of Darolutamide which could result in a higher serum level.
Lansoprazole Lansoprazole may decrease the excretion rate of Darolutamide which could result in a higher serum level.
Erlotinib Erlotinib may decrease the excretion rate of Darolutamide which could result in a higher serum level.
Estradiol Estradiol may decrease the excretion rate of Darolutamide which could result in a higher serum level.
Buprenorphine Buprenorphine may decrease the excretion rate of Darolutamide which could result in a higher serum level.
Telmisartan Telmisartan may decrease the excretion rate of Darolutamide which could result in a higher serum level.
Novobiocin Novobiocin may decrease the excretion rate of Darolutamide which could result in a higher serum level.
Hesperetin Hesperetin may decrease the excretion rate of Darolutamide which could result in a higher serum level.
Rabeprazole Rabeprazole may decrease the excretion rate of Darolutamide which could result in a higher serum level.
Sunitinib Sunitinib may decrease the excretion rate of Darolutamide which could result in a higher serum level.
Genistein Genistein may decrease the excretion rate of Darolutamide which could result in a higher serum level.
Topiroxostat Topiroxostat may decrease the excretion rate of Darolutamide which could result in a higher serum level.
Daidzin Daidzin may decrease the excretion rate of Darolutamide which could result in a higher serum level.
Fusidic acid The metabolism of Darolutamide can be decreased when combined with Fusidic acid.
Naringenin Naringenin may decrease the excretion rate of Darolutamide which could result in a higher serum level.
Quercetin Quercetin may decrease the excretion rate of Darolutamide which could result in a higher serum level.
Taurocholic acid Taurocholic acid may decrease the excretion rate of Darolutamide which could result in a higher serum level.
Elacridar Elacridar may decrease the excretion rate of Darolutamide which could result in a higher serum level.
Vandetanib Vandetanib may decrease the excretion rate of Darolutamide which could result in a higher serum level.
Dovitinib Dovitinib may decrease the excretion rate of Darolutamide which could result in a higher serum level.
Eltrombopag Eltrombopag may decrease the excretion rate of Darolutamide which could result in a higher serum level.
Safinamide Safinamide may decrease the excretion rate of Darolutamide which could result in a higher serum level.
Vismodegib Vismodegib may decrease the excretion rate of Darolutamide which could result in a higher serum level.
Rilpivirine Rilpivirine may decrease the excretion rate of Darolutamide which could result in a higher serum level.
Regorafenib Regorafenib may decrease the excretion rate of Darolutamide which could result in a higher serum level.
Cannabidiol Cannabidiol may decrease the excretion rate of Darolutamide which could result in a higher serum level.
Daclatasvir Daclatasvir may decrease the excretion rate of Darolutamide which could result in a higher serum level.
Dasabuvir Dasabuvir may decrease the excretion rate of Darolutamide which could result in a higher serum level.
Rolapitant Rolapitant may decrease the excretion rate of Darolutamide which could result in a higher serum level.
Paritaprevir Paritaprevir may decrease the excretion rate of Darolutamide which could result in a higher serum level.
Alectinib Alectinib may decrease the excretion rate of Darolutamide which could result in a higher serum level.
Istradefylline Istradefylline may decrease the excretion rate of Darolutamide which could result in a higher serum level.
Fostamatinib Fostamatinib may decrease the excretion rate of Darolutamide which could result in a higher serum level.
Letermovir The excretion of Letermovir can be decreased when combined with Darolutamide.
Gilteritinib Gilteritinib may decrease the excretion rate of Darolutamide which could result in a higher serum level.
Fedratinib The serum concentration of Darolutamide can be increased when it is combined with Fedratinib.
Teniposide Darolutamide may decrease the excretion rate of Teniposide which could result in a higher serum level.
Oxaliplatin Darolutamide may decrease the excretion rate of Oxaliplatin which could result in a higher serum level.
Vincristine Darolutamide may decrease the excretion rate of Vincristine which could result in a higher serum level.
Clofarabine Darolutamide may decrease the excretion rate of Clofarabine which could result in a higher serum level.
Daunorubicin Darolutamide may decrease the excretion rate of Daunorubicin which could result in a higher serum level.
Irinotecan Darolutamide may decrease the excretion rate of Irinotecan which could result in a higher serum level.
Dactinomycin Darolutamide may decrease the excretion rate of Dactinomycin which could result in a higher serum level.
Doxorubicin Darolutamide may decrease the excretion rate of Doxorubicin which could result in a higher serum level.
Mitoxantrone Darolutamide may decrease the excretion rate of Mitoxantrone which could result in a higher serum level.
Copanlisib Darolutamide may decrease the excretion rate of Copanlisib which could result in a higher serum level.
Testosterone cypionate Darolutamide may decrease the excretion rate of Testosterone cypionate which could result in a higher serum level.
Testosterone enanthate Darolutamide may decrease the excretion rate of Testosterone enanthate which could result in a higher serum level.
Estradiol acetate Estradiol acetate may decrease the excretion rate of Darolutamide which could result in a higher serum level.
Estradiol benzoate Estradiol benzoate may decrease the excretion rate of Darolutamide which could result in a higher serum level.
Estradiol cypionate Estradiol cypionate may decrease the excretion rate of Darolutamide which could result in a higher serum level.
Estradiol dienanthate Estradiol dienanthate may decrease the excretion rate of Darolutamide which could result in a higher serum level.
Estradiol valerate Estradiol valerate may decrease the excretion rate of Darolutamide which could result in a higher serum level.
Nabiximols Nabiximols may decrease the excretion rate of Darolutamide which could result in a higher serum level.
Pralatrexate Darolutamide may decrease the excretion rate of Pralatrexate which could result in a higher serum level.
Clofazimine Clofazimine may decrease the excretion rate of Darolutamide which could result in a higher serum level.
Trilaciclib Darolutamide may decrease the excretion rate of Trilaciclib which could result in a higher serum level.
Avanafil The serum concentration of Avanafil can be increased when it is combined with Darolutamide.
Tivozanib Tivozanib may decrease the excretion rate of Darolutamide which could result in a higher serum level.
Belumosudil Belumosudil may decrease the excretion rate of Darolutamide which could result in a higher serum level.
Fluconazole The metabolism of Darolutamide can be decreased when combined with Fluconazole.
Erythromycin The serum concentration of Darolutamide can be increased when it is combined with Erythromycin.
Sildenafil The serum concentration of Darolutamide can be increased when it is combined with Sildenafil.
Reserpine The serum concentration of Darolutamide can be increased when it is combined with Reserpine.
Loxapine The serum concentration of Darolutamide can be increased when it is combined with Loxapine.
Quinine The serum concentration of Darolutamide can be increased when it is combined with Quinine.
Toremifene The serum concentration of Darolutamide can be increased when it is combined with Toremifene.
Simvastatin The serum concentration of Darolutamide can be increased when it is combined with Simvastatin.
Verapamil The metabolism of Darolutamide can be decreased when combined with Verapamil.
Mifepristone The serum concentration of Darolutamide can be increased when it is combined with Mifepristone.
Vardenafil The serum concentration of Darolutamide can be increased when it is combined with Vardenafil.
Tacrolimus The serum concentration of Darolutamide can be increased when it is combined with Tacrolimus.
Quinidine The serum concentration of Darolutamide can be increased when it is combined with Quinidine.
Zonisamide The serum concentration of Darolutamide can be increased when it is combined with Zonisamide.
Carvedilol The serum concentration of Darolutamide can be increased when it is combined with Carvedilol.
Propafenone The serum concentration of Darolutamide can be increased when it is combined with Propafenone.
Lapatinib The serum concentration of Darolutamide can be increased when it is combined with Lapatinib.
Paliperidone The serum concentration of Darolutamide can be increased when it is combined with Paliperidone.
Mibefradil The serum concentration of Darolutamide can be increased when it is combined with Mibefradil.
Biricodar The serum concentration of Darolutamide can be increased when it is combined with Biricodar.
Dronedarone The metabolism of Darolutamide can be decreased when combined with Dronedarone.
Flibanserin The serum concentration of Darolutamide can be increased when it is combined with Flibanserin.

Target Protein

Androgen receptor AR
Progesterone receptor PGR

Referensi & Sumber

Synthesis reference: Pan T, Xia C, Jiang H, Zhang Z, Zhu X, Yang Y.(2017).Chemical Synthesis of the ODM-201's Diastereomers through an Efficient Intramolecular 1,3-Dipolar Cycloaddition.Chem Pharm Bull (Tokyo).Jun 1;65(6):582-585
Artikel (PubMed)
  • PMID: 31571095
    Shore N, Zurth C, Fricke R, Gieschen H, Graudenz K, Koskinen M, Ploeger B, Moss J, Prien O, Borghesi G, Petrenciuc O, Tammela TL, Kuss I, Verholen F, Smith MR, Fizazi K: Evaluation of Clinically Relevant Drug-Drug Interactions and Population Pharmacokinetics of Darolutamide in Patients with Nonmetastatic Castration-Resistant Prostate Cancer: Results of Pre-Specified and Post Hoc Analyses of the Phase III ARAMIS Trial. Target Oncol. 2019 Oct;14(5):527-539. doi: 10.1007/s11523-019-00674-0.
  • PMID: 28801852
    Matsubara N, Mukai H, Hosono A, Onomura M, Sasaki M, Yajima Y, Hashizume K, Yasuda M, Uemura M, Zurth C: Phase 1 study of darolutamide (ODM-201): a new-generation androgen receptor antagonist, in Japanese patients with metastatic castration-resistant prostate cancer. Cancer Chemother Pharmacol. 2017 Dec;80(6):1063-1072. doi: 10.1007/s00280-017-3417-3. Epub 2017 Aug 11.
  • PMID: 31695432
    Bastos DA, Antonarakis ES: Darolutamide For Castration-Resistant Prostate Cancer. Onco Targets Ther. 2019 Oct 23;12:8769-8777. doi: 10.2147/OTT.S197244. eCollection 2019.
  • PMID: 26313416
    Fizazi K, Albiges L, Loriot Y, Massard C: ODM-201: a new-generation androgen receptor inhibitor in castration-resistant prostate cancer. Expert Rev Anticancer Ther. 2015;15(9):1007-17. doi: 10.1586/14737140.2015.1081566.
  • PMID: 30197098
    Fizazi K, Smith MR, Tombal B: Clinical Development of Darolutamide: A Novel Androgen Receptor Antagonist for the Treatment of Prostate Cancer. Clin Genitourin Cancer. 2018 Oct;16(5):332-340. doi: 10.1016/j.clgc.2018.07.017. Epub 2018 Jul 24.

Contoh Produk & Brand

Produk: 4 • International brands: 1
Produk
  • Nubeqa
    Tablet, film coated • 300 mg • Oral • EU • Approved
  • Nubeqa
    Tablet, film coated • 300 mg • Oral • EU • Approved
  • Nubeqa
    Tablet • 300 mg • Oral • Canada • Approved
  • Nubeqa
    Tablet, film coated • 300 mg/1 • Oral • US • Approved
International Brands
  • Nubeqa

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