Peringatan Keamanan

Overdose cases with dasatinib occurred in isolated cases during clinical studies. Patients that received 280 mg of dasatinib per day for 1 week developed severe myelosuppression and bleeding. Since dasatinib is associated with severe myelosuppression, patients that ingest more than the recommended dosage should be monitored closely for myelosuppression and receive appropriate supportive treatment.L45171

Acute overdose in animals was associated with cardiotoxicity. In rodents, ventricular necrosis and valvular/ventricular/atrial hemorrhage were detected at single doses higher than or equal to 100 mg/kg (600 mg/m2). In monkeys receiving single doses higher than or equal to 10 mg/kg (120 mg/m2), there was a tendency for increased systolic and diastolic blood pressure.L45171 In rats, the oral LD50 of dasatinib is 50-100 mg/kg, and in monkeys, it is 25-45 mg/kg.L45176

Dasatinib

DB01254

small molecule approved investigational

Deskripsi

Dasatinib is an orally available multikinase inhibitor indicated for the treatment of Philadelphia chromosome (Ph)-positive leukemias.A2224,L45171 Ph is a chromosomal abnormality found in patients with chronic myelogenous leukemia (CML) and acute lymphocytic leukemia (ALL), where the ABL tyrosine kinase and the breakpoint cluster region (BCR) gene transcribe the chimeric protein BCR-ABL. BCR-ABL is associated with the uncontrolled activity of the ABL tyrosine kinase and is involved in the pathogenesis of CML and 15-30% of ALL cases.A11377,A33432 Dasatinib also inhibits a spectrum of kinases involved in cancer, including several SRC-family kinases.A11377

Unlike imatinib, another tyrosine kinase used for the treatment of CML and Ph-positive ALL, dasatinib inhibits the active and inactive conformations of the ABL kinase domain.A2226,A11377 Also, mutations in the kinase domain of BCR-ABL may lead to relapse during imatinib treatment. Since dasatinib does not interact with some of the residues involved in those mutations, the use of this drug represents a therapeutic alternative for patients with cancers that have developed imatinib-resistance.A2226 The use of dasatinib was first approved by the FDA in 2006.L45171,L45186

Struktur Molekul 2D

Berat 488.006
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 half-life of dasatinib is 3-5 hours.[L45171]
Volume Distribusi Dasatinib has an apparent volume of distribution of 2505 L.[L45171]
Klirens (Clearance) The clearance of dasatinib does not vary over time. Dasatinib has an apparent oral clearance of 363.8 L/hr.[L45171]

Absorpsi

Dasatinib has a dose-proportional pharmacokinetic profile and a linear elimination between 15 mg/day (0.15 times the lowest approved recommended dose) and 240 mg/day (1.7 times the highest approved recommended dose). At 100 mg once a day, dasatinib has a Cmax and AUC of 82.2 ng/mL and 397 ng/mL*hr, respectively. In healthy adult subjects given dasatinib as dispersed tablets in juice, the adjusted geometric mean ratio compared to intact tablets was 0.97 for Cmax, and 0.84 for AUC. The Tmax of dasatinib is between 0.5 and 6 hours following oral administration. Following a single dose of 100 mg, a high-fat meal increases the AUC of dasatinib by 14%.L45171

Metabolisme

In humans, dasatinib is mainly metabolized by CYP3A4, although flavin-containing monooxygenase 3 (FMO3) and uridine diphosphate-glucuronosyltransferase (UGT) enzymes are also involved in the formation of dasatinib metabolites.L45171 Five pharmacologically active dasatinib metabolites have been identified: M4, M5, M6, M20 and M24. M4, M20, and M24 are mainly generated by CYP3A4, M5 is generated by FMO3, and M6 is generated by a cytosolic oxidoreductase.A257226,A15000 M4 is equipotent to dasatinib and represents approximately 5% of the AUC. However, it is unlikely to play a major role in the observed pharmacology of dasatinib.A257226,L45171 M5 and M6 are more than 10 times less active than dasatinib and are considered minor circulating metabolites.A257226

Rute Eliminasi

Dasatinib is mainly eliminated via feces. Within 10 days, 4% of dasatinib is recovered in urine, while 85% is recovered in feces. Approximately 0.1% and 19% of the administered dasatinib dose was recovered unchanged in urine and feces, respectively, and the rest was recovered as metabolites.L45171

Interaksi Makanan

3 Data
  • 1. Avoid grapefruit products. Grapefruit may reduce the CYP3A4 metabolism of dasatinib, increasing its serum levels.
  • 2. Avoid St. John's Wort. This herb induces CYP3A metabolism and may reduce serum levels of dasatinib.
  • 3. Take with or without food. High fat meals may increase the AUC of dasatinib by to 14%; however, the product label recommends taking dasatinib with or without food.

Interaksi Obat

1504 Data
Denosumab The risk or severity of adverse effects can be increased when Denosumab is combined with Dasatinib.
Peginterferon alfa-2a The risk or severity of adverse effects can be increased when Peginterferon alfa-2a is combined with Dasatinib.
Interferon alfa-n1 The risk or severity of adverse effects can be increased when Interferon alfa-n1 is combined with Dasatinib.
Interferon alfa-n3 The risk or severity of adverse effects can be increased when Interferon alfa-n3 is combined with Dasatinib.
Interferon gamma-1b The risk or severity of adverse effects can be increased when Interferon gamma-1b is combined with Dasatinib.
Interferon alfa-2a The risk or severity of adverse effects can be increased when Interferon alfa-2a is combined with Dasatinib.
Gemtuzumab ozogamicin The risk or severity of adverse effects can be increased when Gemtuzumab ozogamicin is combined with Dasatinib.
Pegaspargase The risk or severity of adverse effects can be increased when Pegaspargase is combined with Dasatinib.
Interferon beta-1b The risk or severity of adverse effects can be increased when Interferon beta-1b is combined with Dasatinib.
Interferon alfacon-1 The risk or severity of adverse effects can be increased when Interferon alfacon-1 is combined with Dasatinib.
Rituximab The risk or severity of adverse effects can be increased when Rituximab is combined with Dasatinib.
Basiliximab The risk or severity of adverse effects can be increased when Basiliximab is combined with Dasatinib.
Muromonab The risk or severity of adverse effects can be increased when Muromonab is combined with Dasatinib.
Ibritumomab tiuxetan The risk or severity of adverse effects can be increased when Ibritumomab tiuxetan is combined with Dasatinib.
Tositumomab The risk or severity of adverse effects can be increased when Tositumomab is combined with Dasatinib.
Alemtuzumab The risk or severity of adverse effects can be increased when Alemtuzumab is combined with Dasatinib.
Alefacept The risk or severity of adverse effects can be increased when Alefacept is combined with Dasatinib.
Efalizumab The risk or severity of adverse effects can be increased when Efalizumab is combined with Dasatinib.
Antithymocyte immunoglobulin (rabbit) The risk or severity of adverse effects can be increased when Antithymocyte immunoglobulin (rabbit) is combined with Dasatinib.
Interferon alfa-2b The risk or severity of adverse effects can be increased when Interferon alfa-2b is combined with Dasatinib.
Daclizumab The risk or severity of adverse effects can be increased when Daclizumab is combined with Dasatinib.
Phenylalanine The risk or severity of adverse effects can be increased when Phenylalanine is combined with Dasatinib.
Cladribine The excretion of Cladribine can be decreased when combined with Dasatinib.
Carmustine The risk or severity of adverse effects can be increased when Carmustine is combined with Dasatinib.
Amsacrine The risk or severity of adverse effects can be increased when Amsacrine is combined with Dasatinib.
Bleomycin The risk or severity of adverse effects can be increased when Bleomycin is combined with Dasatinib.
Chlorambucil The risk or severity of adverse effects can be increased when Chlorambucil is combined with Dasatinib.
Raltitrexed The risk or severity of adverse effects can be increased when Raltitrexed is combined with Dasatinib.
Mitomycin The risk or severity of adverse effects can be increased when Mitomycin is combined with Dasatinib.
Floxuridine The risk or severity of adverse effects can be increased when Floxuridine is combined with Dasatinib.
Indomethacin The risk or severity of adverse effects can be increased when Indomethacin is combined with Dasatinib.
Tioguanine The risk or severity of adverse effects can be increased when Tioguanine is combined with Dasatinib.
Dexrazoxane The risk or severity of adverse effects can be increased when Dexrazoxane is combined with Dasatinib.
Streptozocin The risk or severity of adverse effects can be increased when Streptozocin is combined with Dasatinib.
Trifluridine The risk or severity of adverse effects can be increased when Trifluridine is combined with Dasatinib.
Gemcitabine The risk or severity of adverse effects can be increased when Gemcitabine is combined with Dasatinib.
Lenalidomide The risk or severity of adverse effects can be increased when Lenalidomide is combined with Dasatinib.
Altretamine The risk or severity of adverse effects can be increased when Altretamine is combined with Dasatinib.
Cisplatin The risk or severity of adverse effects can be increased when Cisplatin is combined with Dasatinib.
Oxaliplatin The risk or severity of QTc prolongation can be increased when Oxaliplatin is combined with Dasatinib.
Fluorouracil The risk or severity of adverse effects can be increased when Fluorouracil is combined with Dasatinib.
Pentostatin The risk or severity of adverse effects can be increased when Pentostatin is combined with Dasatinib.
Linezolid The risk or severity of adverse effects can be increased when Linezolid is combined with Dasatinib.
Clofarabine The risk or severity of adverse effects can be increased when Clofarabine is combined with Dasatinib.
Pemetrexed The risk or severity of adverse effects can be increased when Pemetrexed is combined with Dasatinib.
Sulfasalazine The risk or severity of adverse effects can be increased when Sulfasalazine is combined with Dasatinib.
Dacarbazine The risk or severity of adverse effects can be increased when Dacarbazine is combined with Dasatinib.
Penicillamine The risk or severity of adverse effects can be increased when Penicillamine is combined with Dasatinib.
Mechlorethamine The risk or severity of adverse effects can be increased when Mechlorethamine is combined with Dasatinib.
Azacitidine The risk or severity of adverse effects can be increased when Azacitidine is combined with Dasatinib.
Carboplatin The risk or severity of adverse effects can be increased when Carboplatin is combined with Dasatinib.
Dactinomycin The risk or severity of adverse effects can be increased when Dactinomycin is combined with Dasatinib.
Azathioprine The risk or severity of adverse effects can be increased when Azathioprine is combined with Dasatinib.
Hydroxyurea The risk or severity of adverse effects can be increased when Hydroxyurea is combined with Dasatinib.
Mycophenolic acid The risk or severity of adverse effects can be increased when Mycophenolic acid is combined with Dasatinib.
Mercaptopurine The risk or severity of adverse effects can be increased when Mercaptopurine is combined with Dasatinib.
Thalidomide The metabolism of Dasatinib can be increased when combined with Thalidomide.
Melphalan The risk or severity of adverse effects can be increased when Melphalan is combined with Dasatinib.
Fludarabine The risk or severity of adverse effects can be increased when Fludarabine is combined with Dasatinib.
Flucytosine The risk or severity of adverse effects can be increased when Flucytosine is combined with Dasatinib.
Capecitabine The risk or severity of adverse effects can be increased when Capecitabine is combined with Dasatinib.
Procarbazine The risk or severity of adverse effects can be increased when Procarbazine is combined with Dasatinib.
Idarubicin The risk or severity of adverse effects can be increased when Idarubicin is combined with Dasatinib.
Eculizumab The risk or severity of adverse effects can be increased when Dasatinib is combined with Eculizumab.
Decitabine The risk or severity of adverse effects can be increased when Dasatinib is combined with Decitabine.
Nelarabine The risk or severity of adverse effects can be increased when Dasatinib is combined with Nelarabine.
Stepronin The risk or severity of adverse effects can be increased when Dasatinib is combined with Stepronin.
Hydroxychloroquine The risk or severity of adverse effects can be increased when Dasatinib is combined with Hydroxychloroquine.
Castanospermine The risk or severity of adverse effects can be increased when Dasatinib is combined with Castanospermine.
Vorinostat The risk or severity of adverse effects can be increased when Dasatinib is combined with Vorinostat.
2-Methoxyethanol The risk or severity of adverse effects can be increased when Dasatinib is combined with 2-Methoxyethanol.
Brequinar The risk or severity of adverse effects can be increased when Dasatinib is combined with Brequinar.
Pirfenidone The risk or severity of adverse effects can be increased when Dasatinib is combined with Pirfenidone.
Interferon alfa The risk or severity of adverse effects can be increased when Dasatinib is combined with Interferon alfa.
Glatiramer The risk or severity of adverse effects can be increased when Dasatinib is combined with Glatiramer.
Briakinumab The risk or severity of adverse effects can be increased when Dasatinib is combined with Briakinumab.
Human interferon omega-1 The risk or severity of adverse effects can be increased when Dasatinib is combined with Human interferon omega-1.
Mepolizumab The risk or severity of adverse effects can be increased when Dasatinib is combined with Mepolizumab.
Abetimus The risk or severity of adverse effects can be increased when Dasatinib is combined with Abetimus.
Belatacept The risk or severity of adverse effects can be increased when Dasatinib is combined with Belatacept.
Bendamustine The risk or severity of adverse effects can be increased when Dasatinib is combined with Bendamustine.
Pralatrexate The risk or severity of adverse effects can be increased when Dasatinib is combined with Pralatrexate.
Wortmannin The risk or severity of adverse effects can be increased when Dasatinib is combined with Wortmannin.
Eribulin The risk or severity of adverse effects can be increased when Dasatinib is combined with Eribulin.
Belimumab The risk or severity of adverse effects can be increased when Dasatinib is combined with Belimumab.
Dimethyl fumarate The risk or severity of adverse effects can be increased when Dasatinib is combined with Dimethyl fumarate.
Obinutuzumab The risk or severity of adverse effects can be increased when Dasatinib is combined with Obinutuzumab.
Vedolizumab The risk or severity of adverse effects can be increased when Dasatinib is combined with Vedolizumab.
Blinatumomab The risk or severity of adverse effects can be increased when Dasatinib is combined with Blinatumomab.
Dinutuximab The risk or severity of adverse effects can be increased when Dasatinib is combined with Dinutuximab.
Tixocortol The risk or severity of adverse effects can be increased when Dasatinib is combined with Tixocortol.
Peginterferon beta-1a The risk or severity of adverse effects can be increased when Dasatinib is combined with Peginterferon beta-1a.
Antilymphocyte immunoglobulin (horse) The risk or severity of adverse effects can be increased when Dasatinib is combined with Antilymphocyte immunoglobulin (horse).
Tepoxalin The risk or severity of adverse effects can be increased when Dasatinib is combined with Tepoxalin.
Ixekizumab The risk or severity of adverse effects can be increased when Dasatinib is combined with Ixekizumab.
Ravulizumab The risk or severity of adverse effects can be increased when Dasatinib is combined with Ravulizumab.
Pirarubicin The risk or severity of adverse effects can be increased when Dasatinib is combined with Pirarubicin.
Peficitinib The risk or severity of adverse effects can be increased when Dasatinib is combined with Peficitinib.
Brodalumab The risk or severity of adverse effects can be increased when Dasatinib is combined with Brodalumab.
Sirukumab The risk or severity of adverse effects can be increased when Dasatinib is combined with Sirukumab.

Target Protein

Tyrosine-protein kinase ABL1 ABL1
Proto-oncogene tyrosine-protein kinase Src SRC
Ephrin type-A receptor 2 EPHA2
Tyrosine-protein kinase Lck LCK
Tyrosine-protein kinase Yes YES1
Mast/stem cell growth factor receptor Kit KIT
Platelet-derived growth factor receptor beta PDGFRB
Tyrosine-protein kinase Fyn FYN
Breakpoint cluster region protein BCR
Signal transducer and activator of transcription 5B STAT5B
Tyrosine-protein kinase ABL2 ABL2
Tyrosine-protein kinase BTK BTK
Nuclear receptor subfamily 4 group A member 3 NR4A3
Tyrosine-protein kinase CSK CSK
Ephrin type-A receptor 5 EPHA5
Ephrin type-B receptor 4 EPHB4
Tyrosine-protein kinase Fgr FGR
Tyrosine-protein kinase FRK FRK
Heat shock cognate 71 kDa protein HSPA8
Tyrosine-protein kinase Lyn LYN
Mitogen-activated protein kinase kinase kinase 20 MAP3K20
Mitogen-activated protein kinase 14 MAPK14
Amidophosphoribosyltransferase PPAT

Referensi & Sumber

Artikel (PubMed)
  • PMID: 17154512
    Das J, Chen P, Norris D, Padmanabha R, Lin J, Moquin RV, Shen Z, Cook LS, Doweyko AM, Pitt S, Pang S, Shen DR, Fang Q, de Fex HF, McIntyre KW, Shuster DJ, Gillooly KM, Behnia K, Schieven GL, Wityak J, Barrish JC: 2-aminothiazole as a novel kinase inhibitor template. Structure-activity relationship studies toward the discovery of N-(2-chloro-6-methylphenyl)-2-[6-[4-(2-hydroxyethyl)-1- piperazinyl)-2-methyl-4-pyrimidinyl]amino)]-1,3-thiazole-5-carboxamide (dasatinib, BMS-354825) as a potent pan-Src kinase inhibitor. J Med Chem. 2006 Nov 16;49(23):6819-32.
  • PMID: 16775234
    Talpaz M, Shah NP, Kantarjian H, Donato N, Nicoll J, Paquette R, Cortes J, O'Brien S, Nicaise C, Bleickardt E, Blackwood-Chirchir MA, Iyer V, Chen TT, Huang F, Decillis AP, Sawyers CL: Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006 Jun 15;354(24):2531-41.
  • PMID: 18420784
    Christopher LJ, Cui D, Wu C, Luo R, Manning JA, Bonacorsi SJ, Lago M, Allentoff A, Lee FY, McCann B, Galbraith S, Reitberg DP, He K, Barros A Jr, Blackwood-Chirchir A, Humphreys WG, Iyer RA: Metabolism and disposition of dasatinib after oral administration to humans. Drug Metab Dispos. 2008 Jul;36(7):1357-64. doi: 10.1124/dmd.107.018267. Epub 2008 Apr 17.
  • PMID: 18556438
    Wang L, Christopher LJ, Cui D, Li W, Iyer R, Humphreys WG, Zhang D: Identification of the human enzymes involved in the oxidative metabolism of dasatinib: an effective approach for determining metabolite formation kinetics. Drug Metab Dispos. 2008 Sep;36(9):1828-39. doi: 10.1124/dmd.107.020255. Epub 2008 Jun 12.
  • PMID: 20072833
    Lindauer M, Hochhaus A: Dasatinib. Recent Results Cancer Res. 2010;184:83-102. doi: 10.1007/978-3-642-01222-8_7.
  • PMID: 19536317
    Aguilera DG, Tsimberidou AM: Dasatinib in chronic myeloid leukemia: a review. Ther Clin Risk Manag. 2009 Apr;5(2):281-9. Epub 2009 May 4.

Contoh Produk & Brand

Produk: 117 • International brands: 0
Produk
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