Peringatan Keamanan

Carcinogenicity studies with dabrafenib have not been conducted. Dabrafenib increased the risk of cutaneous squamous cell carcinomas in patients in clinical trials.L41955

Dabrafenib was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay and was not clastogenic in an in vivo rat bone marrow micronucleus test.L41955

In a combined female fertility and embryo-fetal development study in rats, a reduction in fertility was noted at doses greater than or equal to 20 mg/kg/day (equivalent to the human exposure at the recommended dose based on AUC). A reduction in the number of ovarian corpora lutea was noted in pregnant females at 300 mg/kg/day (which is approximately three times the human exposure at the recommended dose based on AUC).L41955

Male fertility studies with dabrafenib have not been conducted; however, in repeat-dose studies, testicular degeneration/depletion was seen in rats and dogs at doses equivalent to and three times the human exposure at the recommended dose based on AUC, respectively.L41955

Dabrafenib

DB08912

small molecule approved investigational

Deskripsi

Dabrafenib mesylate (Tafinlar) is a reversible ATP-competitive kinase inhibitor and targets the MAPK pathway. It was approved on May 29, 2013, for the treatment of melanoma with V600E or V6000K mutation.L41955 It was also used for metastatic non-small cell lung cancer with the same mutation.L41955

In May 2018, Tafinlar (dabrafenib), in combination with Mekinist (DB08911), was approved to treat anaplastic thyroid cancer caused by an abnormal BRAF V600E gene.L41955

Struktur Molekul 2D

Berat 519.562
Wujud solid

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

Profil Farmakokinetik

Waktu Paruh (Half-Life) The mean terminal half-life of dabrafenib is 8 hours after oral administration. Hydroxy-dabrafenib's terminal half-life (10 hours) parallels that of dabrafenib while the carboxy- and desmethyl-dabrafenib metabolites exhibit longer half-lives (21 to 22 hours).[L41955]
Volume Distribusi The apparent volume of distribution (Vc/F) is 70.3 L.[L41955]Distribution to the brain is restricted because dabrafenib is a substrate and undergoes efflux by P-glycoprotein and breast cancer resistance protein.[A17986]
Klirens (Clearance) The clearance of dabrafenib is 17.0 L/h after single dosing and 34.4 L/h after 2 weeks of twice-daily dosing.[L41955]

Absorpsi

After oral administration, the median time to achieve peak plasma concentration (Tmax) is 2 hours.L41955 Mean absolute bioavailability of oral dabrafenib is 95%.L41955 Following a single dose, dabrafenib exposure (Cmax and AUC) increased in a dose-proportional manner across the dose range of 12 mg to 300 mg, but the increase was less than dose-proportional after repeat twice-daily dosing.L41955 After repeated twice-daily dosing of 150 mg, the mean accumulation ratio was 0.73, and the inter-subject variability (CV%) of AUC at steady-state was 38%.L41955

Metabolisme

The metabolism of dabrafenib is primarily mediated by CYP2C8 and CYP3A4 to form hydroxy-dabrafenib. Hydroxy-dabrafenib is further oxidized via CYP3A4 to form carboxy-dabrafenib and subsequently excreted in bile and urine. Carboxy-dabrafenib is decarboxylated to form desmethyl-dabrafenib; desmethyl-dabrafenib may be reabsorbed from the gut. Desmethyl-dabrafenib is further metabolized by CYP3A4 to oxidative metabolites.L41955

Rute Eliminasi

Fecal excretion is the major route of elimination accounting for 71% of radioactive dose while urinary excretion accounted for 23% of total radioactivity as metabolites only.L41955

Interaksi Makanan

4 Data
  • 1. Avoid grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase the serum levels of dabrafenib.
  • 2. Avoid St. John's Wort. This herb induces CYP3A4 metabolism, which may reduce serum levels of dabrafenib.
  • 3. Do not take with or immediately after a high-fat meal. Dabrafenib's bioavailability is reduced when taken with a high-fat meal.
  • 4. Take on an empty stomach. Take dabrafenib at least one hour before or two hours after a meal.

Interaksi Obat

1545 Data
Modafinil The serum concentration of Modafinil can be decreased when it is combined with Dabrafenib.
Armodafinil The metabolism of Dabrafenib can be increased when combined with Armodafinil.
Aripiprazole The serum concentration of Aripiprazole can be decreased when it is combined with Dabrafenib.
Aripiprazole lauroxil The serum concentration of Aripiprazole lauroxil can be decreased when it is combined with Dabrafenib.
Cilostazol The serum concentration of Cilostazol can be increased when it is combined with Dabrafenib.
Pantoprazole The serum concentration of Pantoprazole can be decreased when it is combined with Dabrafenib.
Citalopram The serum concentration of Citalopram can be decreased when it is combined with Dabrafenib.
Phenytoin The serum concentration of Phenytoin can be decreased when it is combined with Dabrafenib.
Pentobarbital The serum concentration of Pentobarbital can be decreased when it is combined with Dabrafenib.
Amitriptyline The serum concentration of Amitriptyline can be decreased when it is combined with Dabrafenib.
Methadone The serum concentration of Methadone can be decreased when it is combined with Dabrafenib.
Omeprazole The serum concentration of Omeprazole can be decreased when it is combined with Dabrafenib.
Trimethadione The serum concentration of Trimethadione can be decreased when it is combined with Dabrafenib.
Clobazam The serum concentration of Clobazam can be decreased when it is combined with Dabrafenib.
Timolol The serum concentration of Timolol can be decreased when it is combined with Dabrafenib.
Carisoprodol The serum concentration of Carisoprodol can be decreased when it is combined with Dabrafenib.
Progesterone The serum concentration of Progesterone can be decreased when it is combined with Dabrafenib.
Zolpidem The serum concentration of Zolpidem can be decreased when it is combined with Dabrafenib.
Lansoprazole The serum concentration of Lansoprazole can be decreased when it is combined with Dabrafenib.
Imipramine The serum concentration of Imipramine can be decreased when it is combined with Dabrafenib.
Quinine The serum concentration of Quinine can be decreased when it is combined with Dabrafenib.
Fluoxetine The serum concentration of Fluoxetine can be decreased when it is combined with Dabrafenib.
Albendazole The serum concentration of Albendazole can be decreased when it is combined with Dabrafenib.
Cyclophosphamide The serum concentration of Cyclophosphamide can be decreased when it is combined with Dabrafenib.
Voriconazole The serum concentration of Voriconazole can be decreased when it is combined with Dabrafenib.
Doxazosin The serum concentration of Doxazosin can be decreased when it is combined with Dabrafenib.
Thiopental The serum concentration of Thiopental can be decreased when it is combined with Dabrafenib.
Tamoxifen The serum concentration of Tamoxifen can be decreased when it is combined with Dabrafenib.
Thioridazine The serum concentration of Thioridazine can be decreased when it is combined with Dabrafenib.
Esomeprazole The serum concentration of Esomeprazole can be decreased when it is combined with Dabrafenib.
Clopidogrel The serum concentration of Clopidogrel can be decreased when it is combined with Dabrafenib.
Primidone The serum concentration of Primidone can be decreased when it is combined with Dabrafenib.
Diazepam The serum concentration of Diazepam can be decreased when it is combined with Dabrafenib.
Methylphenobarbital The serum concentration of Methylphenobarbital can be decreased when it is combined with Dabrafenib.
Zonisamide The serum concentration of Zonisamide can be decreased when it is combined with Dabrafenib.
Ramelteon The serum concentration of Ramelteon can be decreased when it is combined with Dabrafenib.
Praziquantel The serum concentration of Praziquantel can be decreased when it is combined with Dabrafenib.
Rabeprazole The serum concentration of Rabeprazole can be decreased when it is combined with Dabrafenib.
Proguanil The serum concentration of Proguanil can be decreased when it is combined with Dabrafenib.
Doxepin The serum concentration of Doxepin can be decreased when it is combined with Dabrafenib.
Phenobarbital The serum concentration of Phenobarbital can be decreased when it is combined with Dabrafenib.
Escitalopram The serum concentration of Escitalopram can be decreased when it is combined with Dabrafenib.
Clomipramine The serum concentration of Clomipramine can be decreased when it is combined with Dabrafenib.
Lapatinib The serum concentration of Lapatinib can be decreased when it is combined with Dabrafenib.
Fosphenytoin The serum concentration of Fosphenytoin can be decreased when it is combined with Dabrafenib.
St. John's Wort The serum concentration of St. John's Wort can be decreased when it is combined with Dabrafenib.
Hexobarbital The serum concentration of Hexobarbital can be decreased when it is combined with Dabrafenib.
Acenocoumarol The serum concentration of Acenocoumarol can be decreased when it is combined with Dabrafenib.
Barbital The serum concentration of Barbital can be decreased when it is combined with Dabrafenib.
Methsuximide The serum concentration of Methsuximide can be decreased when it is combined with Dabrafenib.
Lacosamide The serum concentration of Lacosamide can be decreased when it is combined with Dabrafenib.
Etravirine The serum concentration of Etravirine can be decreased when it is combined with Dabrafenib.
Apixaban The serum concentration of Apixaban can be decreased when it is combined with Dabrafenib.
Axitinib The serum concentration of Axitinib can be decreased when it is combined with Dabrafenib.
Artemether The serum concentration of Artemether can be decreased when it is combined with Dabrafenib.
Seratrodast The serum concentration of Seratrodast can be decreased when it is combined with Dabrafenib.
(R)-warfarin The serum concentration of (R)-warfarin can be decreased when it is combined with Dabrafenib.
Vortioxetine The serum concentration of Vortioxetine can be decreased when it is combined with Dabrafenib.
Etizolam The serum concentration of Etizolam can be decreased when it is combined with Dabrafenib.
Esketamine The serum concentration of Esketamine can be decreased when it is combined with Dabrafenib.
Triclabendazole The serum concentration of Triclabendazole can be decreased when it is combined with Dabrafenib.
Lynestrenol The serum concentration of Lynestrenol can be decreased when it is combined with Dabrafenib.
Dexrabeprazole The serum concentration of Dexrabeprazole can be decreased when it is combined with Dabrafenib.
(S)-Warfarin The serum concentration of (S)-Warfarin can be decreased when it is combined with Dabrafenib.
Teniposide The serum concentration of Teniposide can be decreased when it is combined with Dabrafenib.
Propranolol The serum concentration of Propranolol can be decreased when it is combined with Dabrafenib.
Testosterone The serum concentration of Testosterone can be decreased when it is combined with Dabrafenib.
Verapamil The serum concentration of Verapamil can be decreased when it is combined with Dabrafenib.
Paroxetine The serum concentration of Paroxetine can be decreased when it is combined with Dabrafenib.
Estradiol The serum concentration of Estradiol can be decreased when it is combined with Dabrafenib.
Formoterol The serum concentration of Formoterol can be decreased when it is combined with Dabrafenib.
Glyburide The serum concentration of Glyburide can be decreased when it is combined with Dabrafenib.
Sertraline The serum concentration of Sertraline can be decreased when it is combined with Dabrafenib.
Gliclazide The serum concentration of Gliclazide can be decreased when it is combined with Dabrafenib.
Enasidenib The serum concentration of Enasidenib can be decreased when it is combined with Dabrafenib.
Nilutamide The serum concentration of Nilutamide can be decreased when it is combined with Dabrafenib.
Ticlopidine The serum concentration of Ticlopidine can be decreased when it is combined with Dabrafenib.
Dexlansoprazole The serum concentration of Dexlansoprazole can be decreased when it is combined with Dabrafenib.
Fedratinib The serum concentration of Fedratinib can be decreased when it is combined with Dabrafenib.
Pentamidine The serum concentration of Pentamidine can be decreased when it is combined with Dabrafenib.
Cenobamate The serum concentration of Cenobamate can be decreased when it is combined with Dabrafenib.
Labetalol The serum concentration of Labetalol can be decreased when it is combined with Dabrafenib.
Nebivolol The serum concentration of Nebivolol can be decreased when it is combined with Dabrafenib.
Vilazodone The serum concentration of Vilazodone can be decreased when it is combined with Dabrafenib.
Methylene blue The serum concentration of Methylene blue can be decreased when it is combined with Dabrafenib.
Rilpivirine The serum concentration of Rilpivirine can be decreased when it is combined with Dabrafenib.
Stiripentol The metabolism of Dabrafenib can be decreased when combined with Stiripentol.
Valproic acid The serum concentration of Valproic acid can be decreased when it is combined with Dabrafenib.
Moclobemide The serum concentration of Moclobemide can be decreased when it is combined with Dabrafenib.
Selumetinib The serum concentration of Selumetinib can be decreased when it is combined with Dabrafenib.
Benzocaine The serum concentration of Benzocaine can be decreased when it is combined with Dabrafenib.
Eliglustat The metabolism of Eliglustat can be decreased when combined with Dabrafenib.
Ibrutinib The metabolism of Ibrutinib can be decreased when combined with Dabrafenib.
Porfimer sodium Dabrafenib may increase the photosensitizing activities of Porfimer sodium.
Verteporfin Dabrafenib may increase the photosensitizing activities of Verteporfin.
Cimetidine Cimetidine can cause a decrease in the absorption of Dabrafenib resulting in a reduced serum concentration and potentially a decrease in efficacy.
Nizatidine Nizatidine can cause a decrease in the absorption of Dabrafenib resulting in a reduced serum concentration and potentially a decrease in efficacy.
Ranitidine Ranitidine can cause a decrease in the absorption of Dabrafenib resulting in a reduced serum concentration and potentially a decrease in efficacy.
Famotidine Famotidine can cause a decrease in the absorption of Dabrafenib resulting in a reduced serum concentration and potentially a decrease in efficacy.
Methantheline Methantheline can cause a decrease in the absorption of Dabrafenib resulting in a reduced serum concentration and potentially a decrease in efficacy.

Target Protein

Serine/threonine-protein kinase B-raf BRAF
RAF proto-oncogene serine/threonine-protein kinase RAF1
Serine/threonine-protein kinase SIK1 SIK1
Serine/threonine-protein kinase Nek11 NEK11
LIM domain kinase 1 LIMK1

Referensi & Sumber

Artikel (PubMed)
  • PMID: 23621583
    Gibney GT, Zager JS: Clinical development of dabrafenib in BRAF mutant melanoma and other malignancies. Expert Opin Drug Metab Toxicol. 2013 Jul;9(7):893-9. doi: 10.1517/17425255.2013.794220. Epub 2013 Apr 29.
  • PMID: 23249624
    Mittapalli RK, Vaidhyanathan S, Dudek AZ, Elmquist WF: Mechanisms limiting distribution of the threonine-protein kinase B-RaF(V600E) inhibitor dabrafenib to the brain: implications for the treatment of melanoma brain metastases. J Pharmacol Exp Ther. 2013 Mar;344(3):655-64. doi: 10.1124/jpet.112.201475. Epub 2012 Dec 17.
  • PMID: 30422663
    Suo Z, Xiong X, Sun Q, Zhao L, Tang P, Hou Q, Zhang Y, Wu D, Li H: Investigation on the Interaction of Dabrafenib with Human Serum Albumin Using Combined Experiment and Molecular Dynamics Simulation: Exploring the Binding Mechanism, Esterase-like Activity, and Antioxidant Activity. Mol Pharm. 2018 Dec 3;15(12):5637-5645. doi: 10.1021/acs.molpharmaceut.8b00806. Epub 2018 Nov 20.
  • PMID: 25399551
    Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, Lichinitser M, Dummer R, Grange F, Mortier L, Chiarion-Sileni V, Drucis K, Krajsova I, Hauschild A, Lorigan P, Wolter P, Long GV, Flaherty K, Nathan P, Ribas A, Martin AM, Sun P, Crist W, Legos J, Rubin SD, Little SM, Schadendorf D: Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015 Jan 1;372(1):30-9. doi: 10.1056/NEJMoa1412690. Epub 2014 Nov 16.
  • PMID: 27569556
    Millet A, Martin AR, Ronco C, Rocchi S, Benhida R: Metastatic Melanoma: Insights Into the Evolution of the Treatments and Future Challenges. Med Res Rev. 2017 Jan;37(1):98-148. doi: 10.1002/med.21404. Epub 2016 Aug 29.
  • PMID: 22554099
    Ascierto PA, Kirkwood JM, Grob JJ, Simeone E, Grimaldi AM, Maio M, Palmieri G, Testori A, Marincola FM, Mozzillo N: The role of BRAF V600 mutation in melanoma. J Transl Med. 2012 Jul 9;10:85. doi: 10.1186/1479-5876-10-85.
  • PMID: 22175026
    Sullivan RJ, Flaherty KT: BRAF in Melanoma: Pathogenesis, Diagnosis, Inhibition, and Resistance. J Skin Cancer. 2011;2011:423239. doi: 10.1155/2011/423239. Epub 2011 Nov 17.
  • PMID: 17126425
    McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Wong EW, Chang F, Lehmann B, Terrian DM, Milella M, Tafuri A, Stivala F, Libra M, Basecke J, Evangelisti C, Martelli AM, Franklin RA: Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta. 2007 Aug;1773(8):1263-84. doi: 10.1016/j.bbamcr.2006.10.001. Epub 2006 Oct 7.
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