Dasatinib

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Dasatinib
Clinical data
Trade namesSprycel
AHFS/Drugs.comMonograph
MedlinePlusa607063
License data
Pregnancy
category
  • AU: D
Routes of
administration		Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding96%
MetabolismHepatic
Elimination half-life1.3 to 5 hours
ExcretionFaecal (85%), renal (4%)
Identifiers
  • N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-
    1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole
    carboxamide monohydrate
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.228.321 Edit this at Wikidata
Chemical and physical data
FormulaC22H26ClN7O2S
Molar mass488.01 g/mol g·mol−1
3D model (JSmol)
  • Cc1cccc(c1NC(=O)c2cnc(s2)Nc3cc(nc(n3)C)N4CCN(CC4)CCO)Cl
  • InChI=1S/C22H26ClN7O2S/c1-14-4-3-5-16(23)20(14)28-21(32)17-13-24-22(33-17)27-18-12-19(26-15(2)25-18)30-8-6-29(7-9-30)10-11-31/h3-5,12-13,31H,6-11H2,1-2H3,(H,28,32)(H,24,25,26,27) checkY
  • Key:ZBNZXTGUTAYRHI-UHFFFAOYSA-N checkY=  checkY
 ☒NcheckY (what is this?)  (verify)

Dasatinib, previously known as BMS-354825, is a cancer drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel. Dasatinib is an oral multi- BCR/Abl and Src family tyrosine kinase inhibitor approved for first line use in patients with chronic myelogenous leukemia (CML)[1] and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). It is being evaluated for use in numerous other cancers, including advanced prostate cancer.

The drug is named after one of the inventor chemists, Jagabandhu Das, who was a member of the large discovery and development team at Bristol Myers Squibb.[2]

Origin and development

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.[3] Complete hematological responses[4] were seen in 37 of 40 patients with chronic-phase CML. Major hematologic responses were seen in 31 of 44 patients with accelerated-phase CML, CML in blast crisis, or Ph+ ALL.

Molecular targets

Crystal structure[5] (PDB 2GQG) of Abl kinase domain (blue) in complex with dasatinib (red).

The main targets of dasatinib are BCR/Abl, Src, c-Kit, ephrin receptors, and several other tyrosine kinases, but not erbB kinases such as EGFR or Her2.

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.

Susceptible genotypes

Responses were seen in patients with all BCR/Abl genotypes, with the exception of T315I mutation, which confers resistance to dasatinib, nilotinib and imatinib in vitro.

Toxicities

Neutropenia and myelosuppression were common toxic effects. Fifteen patients (of 84, i.e. 18%) 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.Several cases of pulmonary arterial hypertension (PAH) were found in patients treated with dasatinib.[6]

Adverse effects

On October 11, 2011 the U.S. Food and Drug Administration (FDA) announced that dasatinib may increase the risk of a rare but serious condition in which there is abnormally high blood pressure in the arteries of the lungs (pulmonary hypertension, PAH). Symptoms of PAH may include shortness of breath, fatigue, and swelling of the body (such as the ankles and legs). In reported cases, patients developed PAH after starting dasatinib, including after more than one year of treatment.

Information about this risk has been added to the Warnings and Precautions section of the Sprycel drug label.[7]

See also

Cost

The Union for Affordable Cancer Treatment objected to the price of dasatinib, in a letter to the U.S. trade representative. The average wholesale price in the U.S. is $367 per day, twice the price in other high income countries. The price in India, where the average annual per capita income is $1,570, and where most patients pay out of pocket, is Rs6627 ($108) a day. Indian manufacturers offered to supply generic versions for $4 a day, but, under pressure from the U.S., the Indian Department of Industrial Policy and Promotion refused to issue a compulsory license.[8]

Bristol-Myers Squibb justified the high prices of cancer drugs with the high R&D costs, but the Union of Affordable Cancer Treatment said that most of the R&D costs came from the U.S. government, including National Institutes of Health funded research and clinical trials, and a 50% tax credit. In England and Wales, the National Institute for Health and Care Excellence recommended against dasatinib because of the high cost-benefit ratio.[8]

The Union for Affordable Cancer Treatment said that “the dasatinib dispute illustrates the shortcomings of US trade policy and its impact on cancer patients.”[8]

References

  1. ^ FDA. "FDA approves additional medical indication for Sprycel". www.fda.gov. FDA. Retrieved 22 March 2013.
  2. ^ 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. doi:10.1021/jm060727j. PMID 17154512. {{cite journal}}: Explicit use of et al. in: |author= (help)
  3. ^ Talpaz M, Shah NP, Kantarjian H; et al. (June 2006). "Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias". N. Engl. J. Med. 354 (24): 2531–41. doi:10.1056/NEJMoa055229. PMID 16775234. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  4. ^ 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.
  5. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 16740718, please use {{cite journal}} with |pmid=16740718 instead.
  6. ^ NHS - Healthcare News
  7. ^ FDA: Sprycel (dasatinib): Drug Safety Communication - Risk of Pulmonary Arterial Hypertension, 10/11/2011.
  8. ^ a b c Deborah Cohen (04 November 2014). "US trade rep is pressing Indian government to forbid production of generic cancer drug, consortium says". BMJ. 349: g6593. doi:10.1136/bmj.g6593. {{cite journal}}: Check date values in: |date= (help)

External links

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