Dasatinib
Encyclopedia
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 use in patients with chronic myelogenous leukemia
(CML) after imatinib
treatment 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.
dose escalation study published in June 2006, dasatinib was tested in patients who were resistant to or who could not tolerate imatinib
. Complete hematological responses 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.
, c-Kit, ephrin receptors, and several other tyrosine kinases, but not erbB kinases such as EGFR or Her2.
genotypes, with the exception of T315I mutation, which confers resistance to both dasatinib, nilotinib and imatinib
in vitro.
and myelosuppression were common toxic effects. Fifteen patients (of 84, ie 18%) in the above-mentioned study developed pleural effusion
s, 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.
(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.
And information about this risk has been added to the Warnings and Precautions section of the Sprycel drug label.
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
produced by Bristol-Myers Squibb
Bristol-Myers Squibb
Bristol-Myers Squibb , often referred to as BMS, is a pharmaceutical company, headquartered in New York City. The company was formed in 1989, following the merger of its predecessors Bristol-Myers and the Squibb Corporation...
and sold under the trade name Sprycel. Dasatinib is an oral multi- BCR/ABL
Philadelphia chromosome
Philadelphia chromosome or Philadelphia translocation is a specific chromosomal abnormality that is associated with chronic myelogenous leukemia . It is the result of a reciprocal translocation between chromosome 9 and 22, and is specifically designated t...
and Src
Src (gene)
Proto-oncogene tyrosine-protein kinase Src is an enzyme that in humans is encoded by the SRC gene.Src is a proto-oncogene encoding a tyrosine kinase originally discovered by J. Michael Bishop and Harold E. Varmus, for which they won the 1989 Nobel Prize in Physiology or Medicine. It belongs to a...
family tyrosine kinase inhibitor approved for use in patients with chronic myelogenous leukemia
Chronic myelogenous leukemia
Chronic myelogenous leukemia , also known as chronic granulocytic leukemia , is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of predominantly myeloid cells in the bone marrow and the accumulation of these cells in the blood...
(CML) after imatinib
Imatinib
Imatinib is a drug used to treat certain types of cancer. It is currently marketed by Novartis as Gleevec or Glivec as its mesylate salt, imatinib mesilate . It is used in treating chronic myelogenous leukemia , gastrointestinal stromal tumors and some other diseases...
treatment and Philadelphia chromosome
Philadelphia chromosome
Philadelphia chromosome or Philadelphia translocation is a specific chromosomal abnormality that is associated with chronic myelogenous leukemia . It is the result of a reciprocal translocation between chromosome 9 and 22, and is specifically designated t...
-positive acute lymphoblastic leukemia
Acute lymphoblastic leukemia
Acute lymphoblastic leukemia is a form of leukemia, or cancer of the white blood cells characterized by excess lymphoblasts.Malignant, immature white blood cells continuously multiply and are overproduced in the bone marrow. ALL causes damage and death by crowding out normal cells in the bone...
(Ph+ ALL). It is being evaluated for use in numerous other cancers, including advanced prostate cancer
Prostate cancer
Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...
.
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.
Efficacy
In a Phase IClinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
dose escalation study published in June 2006, dasatinib was tested in patients who were resistant to or who could not tolerate imatinib
Imatinib
Imatinib is a drug used to treat certain types of cancer. It is currently marketed by Novartis as Gleevec or Glivec as its mesylate salt, imatinib mesilate . It is used in treating chronic myelogenous leukemia , gastrointestinal stromal tumors and some other diseases...
. Complete hematological responses 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
The main targets of dasatinib, are BCR/ABL, SrcSrc (gene)
Proto-oncogene tyrosine-protein kinase Src is an enzyme that in humans is encoded by the SRC gene.Src is a proto-oncogene encoding a tyrosine kinase originally discovered by J. Michael Bishop and Harold E. Varmus, for which they won the 1989 Nobel Prize in Physiology or Medicine. It belongs to a...
, 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/ABLPhiladelphia chromosome
Philadelphia chromosome or Philadelphia translocation is a specific chromosomal abnormality that is associated with chronic myelogenous leukemia . It is the result of a reciprocal translocation between chromosome 9 and 22, and is specifically designated t...
genotypes, with the exception of T315I mutation, which confers resistance to both dasatinib, nilotinib and imatinib
Imatinib
Imatinib is a drug used to treat certain types of cancer. It is currently marketed by Novartis as Gleevec or Glivec as its mesylate salt, imatinib mesilate . It is used in treating chronic myelogenous leukemia , gastrointestinal stromal tumors and some other diseases...
in vitro.
Toxicities
NeutropeniaNeutropenia
Neutropenia, from Latin prefix neutro- and Greek suffix -πενία , is a granulocyte disorder characterized by an abnormally low number of neutrophils, the most important type of white blood cell...
and myelosuppression were common toxic effects. Fifteen patients (of 84, ie 18%) in the above-mentioned study developed pleural effusion
Pleural effusion
Pleural effusion is excess fluid that accumulates between the two pleural layers, the fluid-filled space that surrounds the lungs. Excessive amounts of such fluid can impair breathing by limiting the expansion of the lungs during ventilation.-Pathophysiology:...
s, which were felt to be a side effect of dasatinib. Some of these patients required thoracentesis
Thoracentesis
Thoracentesis , also known as thoracocentesis or pleural tap, is an invasive procedure to remove fluid or air from the pleural space for diagnostic or therapeutic purposes. A cannula, or hollow needle, is carefully introduced into the thorax, generally after administration of local anesthesia...
or pleurodesis
Pleurodesis
Pleurodesis is a medical procedure in which the pleural space is artificially obliterated. It involves the adhesion of the two pleura.- Uses :Pleurodesis is done to prevent recurrence of pneumothorax or recurrent pleural effusion...
to treat the effusions. Other adverse events included mild to moderate diarrhea, peripheral edema
Edema
Edema or oedema ; both words from the Greek , oídēma "swelling"), formerly known as dropsy or hydropsy, is an abnormal accumulation of fluid beneath the skin or in one or more cavities of the body that produces swelling...
, and headache
Headache
A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
. A small number of patients developed abnormal liver function tests
Liver function tests
Liver function tests , are groups of clinical biochemistry laboratory blood assays designed to give information about the state of a patient's liver. The parameters measured include PT/INR, aPTT, albumin, billirubin and others...
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.
Adverse effects
On October 11, 2011 the U.S. Food and Drug AdministrationFood and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(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
Pulmonary hypertension
In medicine, pulmonary hypertension is an increase in blood pressure in the pulmonary artery, pulmonary vein, or pulmonary capillaries, together known as the lung vasculature, leading to shortness of breath, dizziness, fainting, and other symptoms, all of which are exacerbated by exertion...
, 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.
And information about this risk has been added to the Warnings and Precautions section of the Sprycel drug label.