Dasatinib
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Dasatinib
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| Systematic (IUPAC) name | |
| N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)- 1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide monohydrate |
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| Identifiers | |
| CAS number | |
| ATC code | L01 |
| PubChem | |
| Chemical data | |
| Formula | C22H26ClN7O2S |
| Mol. mass | 488.01 g/mol |
| Pharmacokinetic data | |
| Bioavailability | ? |
| Protein binding | 96% |
| Metabolism | Hepatic |
| Half life | 1.3 to 5 hours |
| Excretion | Fecal (85%), renal (4%) |
| Therapeutic considerations | |
| Licence data |
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| Pregnancy cat. | |
| Legal status | |
| Routes | Oral |
Dasatinib, also known as BMS-354825, is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel®. Dasatinib is an oral dual BCR/ABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). It is also being assessed for use in metastatic melanoma. The drug is named after the inventor chemist, Jagabandhu Das, who codiscovered it while working at Bristol Myers Squibb.[1]
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[edit] Efficacy
In a Phase I dose escalation study published in June 2006, dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al., 2006). Complete hematological responses[2] were seen in 37 of 40 patients with chronic-phase CML. Major hematologic responses[3] were seen in 31 of 44 patients with accelerated-phase CML, CML in blast crisis, or Ph+ ALL.
[edit] Duration of benefit
Responses were maintained in 95% of patients with chronic-phase CML, with a median follow-up time of >12 months. In patients with accelerated-phase CML, 82% remained in remission, although with a median follow-up of only 5 months. Nearly all patients with CML in blast crisis or Ph+ ALL relapsed within 6 months.
[edit] Susceptible genotypes
Responses were seen in patients with all BCR/ABL genotypes, with the exception of T315I mutation, which confers resistance to both dasatinib and imatinib in vitro.
[edit] Toxicities
Neutropenia and myelosuppression were common toxic effects. Fifteen patients in the above-mentioned study developed pleural effusions, which were felt to be a side effect of dasatinib. Some of these patients required thoracentesis or pleurodesis to treat the effusions. Other adverse events included mild to moderate diarrhea, peripheral edema, and headache. A small number of patients developed abnormal liver function tests which returned to normal without dose adjustments. Mild hypocalcemia was also noted, but did not appear to cause any significant problems.
[edit] Notes
- ^ Das J et al. (2006). "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 49 (23): 6819-32. PMID 17154512.
- ^ Complete hematologic response was defined as normal white blood cell and platelet counts, no blasts in the peripheral blood, <5% myelocytes plus metamyelocytes in the peripheral blood, <20% basophils in the peripheral blood, and no extramedullary disease.
- ^ The definition of a major hematologic response was sufficiently abstruse that the reader is referred to the original article (Talpaz et al., 2006) for details.
[edit] Reference
- Talpaz M, Shah N, Kantarjian H, Donato N, Nicoll J, Paquette R, Cortes J, O'Brien S, Nicaise C, Bleickardt E, Blackwood-Chirchir M, Iyer V, Chen T, Huang F, Decillis A, Sawyers C (2006). "Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias". N Engl J Med 354 (24): 2531-41. PMID 16775234.
[edit] External links
- Summary Basis for Approval from the U.S. Food and Drug Administration Freedom of Information homepage
- Prescribing information from Bristol-Myers Squibb
- Diary of a CML patient involved in the clinical trials for dasatinib
