Sprycel
   HOME

TheInfoList



OR:

Dasatinib, sold under the brand name Sprycel among others, is a
targeted therapy Targeted therapy or molecularly targeted therapy is one of the major modalities of medical treatment (pharmacotherapy) for cancer, others being hormonal therapy (oncology), hormonal therapy and cytotoxic chemotherapy. As a form of molecular medici ...
medication used to treat certain cases of
chronic myelogenous leukemia Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of myeloid cells in the bone marrow and the accumula ...
(CML) and
acute lymphoblastic leukemia Acute lymphoblastic leukemia (ALL) is a cancer of the Lymphocyte, lymphoid line of blood cells characterized by the development of large numbers of lymphoblast, immature lymphocytes. Symptoms may include feeling tired, pale skin color, fever, ...
(ALL). Specifically it is used to treat cases that are
Philadelphia chromosome The Philadelphia chromosome or Philadelphia translocation (Ph) is an abnormal version of chromosome 22 where a part of the ''ABL (gene), Abelson murine leukemia'' 1 (''ABL1'') gene on chromosome 9 breaks off and attaches to the ''BCR (gene), break ...
-positive (Ph+). It is taken
by mouth Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...
. Common
adverse effect An adverse effect is an undesired harmful effect resulting from a medication or other intervention, such as surgery. An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. The term compli ...
s include
low white blood cells Leukopenia () is a decrease in the number of white blood cells (leukocytes). It places individuals at increased risk of infection as white blood cells are the body's primary defense against infections. Signs and symptoms Symptoms may include: * sk ...
, low blood platelets,
anemia Anemia (also spelt anaemia in British English) is a blood disorder in which the blood has a reduced ability to carry oxygen. This can be due to a lower than normal number of red blood cells, a reduction in the amount of hemoglobin availabl ...
, swelling, rash, and diarrhea. Severe adverse effects may include bleeding,
pulmonary edema Pulmonary edema (British English: oedema), also known as pulmonary congestion, is excessive fluid accumulation in the tissue or air spaces (usually alveoli) of the lungs. This leads to impaired gas exchange, most often leading to shortness ...
,
heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome caused by an impairment in the heart's ability to Cardiac cycle, fill with and pump blood. Although symptoms vary based on which side of the heart is affected, HF ...
, and prolonged QT syndrome. Use during
pregnancy Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...
may result in harm to the fetus. It is a tyrosine-kinase inhibitor and works by blocking a number of
tyrosine kinases -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a conditionally essential amino acid with a polar side group. The word "tyrosine" is ...
such as
Bcr-Abl The Philadelphia chromosome or Philadelphia translocation (Ph) is an abnormal version of chromosome 22 where a part of the '' Abelson murine leukemia'' 1 (''ABL1'') gene on chromosome 9 breaks off and attaches to the '' breakpoint cluster region'' ...
and the Src kinase family. Dasatinib was approved for medical use in the United States and in the European Union in 2006. It is on the
World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health s ...
.


Medical uses

Dasatinib is used to treat people with
chronic myeloid leukemia Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of myeloid cells in the bone marrow and the accumula ...
and people with
acute lymphoblastic leukemia Acute lymphoblastic leukemia (ALL) is a cancer of the Lymphocyte, lymphoid line of blood cells characterized by the development of large numbers of lymphoblast, immature lymphocytes. Symptoms may include feeling tired, pale skin color, fever, ...
who are positive for the
Philadelphia chromosome The Philadelphia chromosome or Philadelphia translocation (Ph) is an abnormal version of chromosome 22 where a part of the ''ABL (gene), Abelson murine leukemia'' 1 (''ABL1'') gene on chromosome 9 breaks off and attaches to the ''BCR (gene), break ...
. In the EU dasatinib is indicated for children with * newly diagnosed Philadelphia chromosome-positive chronic myelogenous leukaemia in chronic phase (Ph+ CML CP) or Ph+ CML CP resistant or intolerant to prior therapy including imatinib. * newly diagnosed Ph+ acute lymphoblastic leukaemia (ALL) in combination with chemotherapy. * newly diagnosed Ph+ CML in chronic phase (Ph+ CML-CP) or Ph+ CML-CP resistant or intolerant to prior therapy including imatinib. and adults with * newly diagnosed Philadelphia-chromosome-positive (Ph+) chronic myelogenous leukaemia (CML) in the chronic phase; * chronic, accelerated or blast phase CML with resistance or intolerance to prior therapy including imatinib mesilate; * Ph+ acute lymphoblastic leukaemia (ALL) and lymphoid blast CML with resistance or intolerance to prior therapy.


Adverse effects

The most common side effects are
infection An infection is the invasion of tissue (biology), tissues by pathogens, their multiplication, and the reaction of host (biology), host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmis ...
, suppression of the bone marrow (decreasing numbers of
leukocyte White blood cells (scientific name leukocytes), also called immune cells or immunocytes, are cells of the immune system that are involved in protecting the body against both infectious disease and foreign entities. White blood cells are genera ...
s,
erythrocyte Red blood cells (RBCs), referred to as erythrocytes (, with -''cyte'' translated as 'cell' in modern usage) in academia and medical publishing, also known as red cells, erythroid cells, and rarely haematids, are the most common type of blood ce ...
s, and
thrombocyte Platelets or thrombocytes () are a part of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping to form a blood clot. Platelets have no cell nucleus; they are fragments of cytop ...
s),
headache A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of Depression (mood), depression in those with severe ...
, hemorrhage (bleeding),
pleural effusion A pleural effusion is accumulation of excessive fluid in the pleural space, the potential space that surrounds each lung. Under normal conditions, pleural fluid is secreted by the parietal pleural capillaries at a rate of 0.6 millilitre per kilog ...
(fluid around the lungs),
dyspnea Shortness of breath (SOB), known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing discomfort that ...
(difficulty breathing),
diarrhea Diarrhea (American English), also spelled diarrhoea or diarrhœa (British English), is the condition of having at least three loose, liquid, or watery bowel movements in a day. It often lasts for a few days and can result in dehydration d ...
,
vomiting Vomiting (also known as emesis, puking and throwing up) is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteritis, pre ...
,
nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...
(feeling sick),
abdominal pain Abdominal pain, also known as a stomach ache, is a symptom associated with both non-serious and serious medical issues. Since the abdomen contains most of the body's vital organs, it can be an indicator of a wide variety of diseases. Given th ...
(belly ache),
skin rash A rash is a change of the skin that affects its color, appearance, or texture. A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, cracked ...
, musculoskeletal pain,
tiredness Fatigue is a state of tiredness (which is not sleepiness), exhaustion or loss of energy. It is a symptom of any of various diseases; it is not a disease in itself. Fatigue (in the medical sense) is sometimes associated with medical conditions ...
, swelling in the legs and arms and in the face,
fever Fever or pyrexia in humans is a symptom of an anti-infection defense mechanism that appears with Human body temperature, body temperature exceeding the normal range caused by an increase in the body's temperature Human body temperature#Fever, s ...
.
Neutropenia Neutropenia is an abnormally low concentration of neutrophils (a type of white blood cell) in the blood. Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteria ...
and
myelosuppression Bone marrow suppression also known as myelotoxicity or myelosuppression, is the decrease in production of cells responsible for providing immunity (leukocytes), carrying oxygen (erythrocytes), and/or those responsible for normal blood clotting ( ...
were common toxic effects. Fifteen people (of 84, i.e. 18%) in the above-mentioned study developed
pleural effusion A pleural effusion is accumulation of excessive fluid in the pleural space, the potential space that surrounds each lung. Under normal conditions, pleural fluid is secreted by the parietal pleural capillaries at a rate of 0.6 millilitre per kilog ...
s, which was a suspected side effect of dasatinib. Some of these people required
thoracentesis Thoracentesis , also known as thoracocentesis (), pleural tap, needle thoracostomy, or needle decompression (often used term), is an invasive medical procedure to remove fluid or air from the pleural space for diagnostic or therapeutic purposes. ...
or
pleurodesis Pleurodesis is a medical procedure in which part of the pleural space is artificially obliterated. It involves the adhesion of the visceral and the costal pleura. The mediastinal pleura is spared. Uses Pleurodesis is performed to prevent recurr ...
to treat the effusions. Other adverse events included mild to moderate diarrhea, peripheral
edema Edema (American English), also spelled oedema (British English), and also known as fluid retention, swelling, dropsy and hydropsy, is the build-up of fluid in the body's tissue (biology), tissue. Most commonly, the legs or arms are affected. S ...
, and
headache A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of Depression (mood), depression in those with severe ...
. A small number of people developed abnormal
liver function tests Liver function tests (LFTs or LFs), also referred to as a hepatic panel or liver panel, are groups of blood tests that provide information about the state of a patient's liver. These tests include prothrombin time (PT/INR), activated partial ...
which returned to normal without dose adjustments. Mild
hypocalcemia Hypocalcemia is a medical condition characterized by low calcium levels in the blood serum. The normal range of blood calcium is typically between 2.1–2.6  mmol/L (8.8–10.7 mg/dL, 4.3–5.2 mEq/L), while levels less than 2.1  ...
was also noted, but did not appear to cause any significant problems. Several cases of
pulmonary arterial hypertension Pulmonary arterial hypertension (PAH) is a syndrome in which the blood pressure in the pulmonary arteries and pulmonary arterioles (the blood vessels located proximal to the capillary bed, the site of oxygen exchange in the lungs) is elevated. T ...
(PAH) were found in people treated with dasatinib, possibly due to pulmonary
endothelial cell The endothelium (: endothelia) is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and th ...
damage. On 11 October 2011, the U.S.
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
(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 (PH or PHTN) is a condition of increased blood pressure in the pulmonary artery, arteries of the lungs. Symptoms include dypsnea, shortness of breath, Syncope (medicine), fainting, tiredness, chest pain, pedal edema, swell ...
, PAH). Symptoms of PAH may include shortness of breath, fatigue, and swelling of the body (such as the ankles and legs). In reported cases, people developed PAH after starting dasatinib, including after more than one year of treatment. Information about the risk was added to the Warnings and Precautions section of the Sprycel drug label. In studies between 2009 and 2017 dasatinib-induced PAH was initiated between 0.3 and 74 months of daily drug usage at doses from 70 to 140 mg. Reported dasatinib-induced PAH had improvements after cessation of drug treatment.


Pharmacology

Dasatinib is an ATP-competitive protein
tyrosine kinase inhibitor A tyrosine kinase inhibitor (TKI) is a pharmaceutical drug that inhibits tyrosine kinases. Tyrosine kinases are enzymes responsible for the activation of many proteins by signal transduction cascades. The proteins are activated by adding a phosph ...
. The main targets of dasatinib are BCR/Abl (the "Philadelphia chromosome"), Src,
c-Kit Proto-oncogene c-KIT is the gene encoding the receptor tyrosine kinase protein known as tyrosine-protein kinase KIT, CD117 (cluster of differentiation 117) or mast/stem cell growth factor receptor (SCFR). Multiple transcript variants encoding dif ...
,
ephrin receptor Eph receptors (Ephs, after erythropoietin-producing human hepatocellular receptors) are a group of receptor (biochemistry), receptors that are activated in response to binding with Ephrin, Eph receptor-interacting proteins (Ephrins). Ephs form th ...
s, and several other tyrosine kinases. Strong inhibition of the activated BCR-ABL kinase distinguishes dasatinib from other CML treatments, such as
imatinib Imatinib, sold under the brand names Gleevec and Glivec (both marketed worldwide by Novartis) among others, is an oral targeted therapy medication used to treat cancer. Imatinib is a small molecule inhibitor targeting multiple tyrosine kinases ...
and
nilotinib Nilotinib, sold under the brand name Tasigna among others, is an anti-cancer medication used to treat chronic myelogenous leukemia (CML) which has the Philadelphia chromosome. It may be used both in initial cases of chronic phase CML as well a ...
. Although dasatinib only has a
plasma half-life Biological half-life (elimination half-life, pharmacological half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the blood plasma. ...
of three to five hours, the strong binding to BCR-ABL1 results in a longer duration of action.


History

Dasatinib was developed by collaboration of
Bristol-Myers Squibb The Bristol-Myers Squibb Company, doing business as Bristol Myers Squibb (BMS), is an American multinational pharmaceutical company. Headquartered in Princeton, New Jersey, BMS is one of the world's largest pharmaceutical companies and consist ...
and Otsuka Pharmaceutical Co., Ltd, and named for Bristol-Myers Squibb research fellow Jagabandhu Das, whose program leader says that the drug would not have come into existence had he not challenged some of the
medicinal chemist Medicinal or pharmaceutical chemistry is a scientific discipline at the intersection of chemistry and pharmacy involved with designing and developing pharmaceutical drugs. Medicinal chemistry involves the identification, synthesis and developmen ...
s' underlying assumptions at a time when progress in the development of the molecule had stalled.


Society and culture


Legal status

Dasatinib was approved for use in the United States in June 2006 and in the European Union in November 2006 In October 2010, dasatinib was approved in the United States for the treatment of newly diagnosed adults with Philadelphia chromosome positive chronic myeloid leukemia in chronic phase (CP-CML). In November 2017, dasatinib was approved in the United States for the treatment of children with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in the chronic phase. Approval was based on data from 97 pediatric participants with chronic phase CML evaluated in two trials—a Phase I, open-label, non-randomized, dose-ranging trial and a Phase II, open-label, non-randomized trial. Fifty-one participants exclusively from the Phase II trial were newly diagnosed with chronic phase CML and 46 participants (17 from the Phase I trial and 29 from the Phase II trial) were resistant or intolerant to previous treatment with imatinib. The majority of participants were treated with dasatinib tablets 60 mg/m2
body surface area In physiology and medicine, the body surface area (BSA) is the measured or calculated surface area of a human body. For many clinical purposes, BSA is a better indicator of metabolic mass than body weight because it is less affected by abnormal ad ...
once daily. Participants were treated until disease progression or unacceptable toxicity.


Economics

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 people 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. 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. The Union for Affordable Cancer Treatment said that "the dasatinib dispute illustrates the shortcomings of US trade policy and its impact on cancer patients"


Brand names

In
Bangladesh Bangladesh, officially the People's Republic of Bangladesh, is a country in South Asia. It is the List of countries and dependencies by population, eighth-most populous country in the world and among the List of countries and dependencies by ...
dasatinib is available under the trade name Dasanix by Beacon Pharmaceuticals. In India, It is marketed under the brand name Nextki by Emcure Pharmaceuticals.


Research

Dasatinib has been shown to eliminate senescent cells in cultured adipocyte progenitor cells.


Dasatinib+Quercetin

Dasatinib has been shown to induce apoptosis in senescent cells by inhibiting Src kinase, whereas
quercetin Quercetin is a plant flavonol from the flavonoid group of polyphenols. It is found in many fruits, vegetables, leaves, seeds, and grains; capers, red onions, and kale are common foods containing appreciable amounts of it. It has a bitter flavor ...
inhibits the anti-apoptotic protein
Bcl-xL B-cell lymphoma-extra large (Bcl-xL), encoded by the BCL2-like 1 gene, is a transmembrane molecule in the mitochondria. It is a member of the Bcl-2 family of proteins, and acts as an anti-apoptotic protein by preventing the release of mitochondr ...
. Administration of dasatinib along with quercetin to mice improved
cardiovascular In vertebrates, the circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the body. It includes the cardiovascular system, or vascular system, that consists of the heart a ...
function and eliminated senescent cells. Aged mice given dasatinib with quercetin showed improved health and survival. A study of fourteen human patients with
idiopathic pulmonary fibrosis Idiopathic pulmonary fibrosis (IPF) synonymous with cryptogenic fibrosing alveolitis is a rare, progressive illness of the respiratory system, characterized by the thickening and stiffening of lung tissue, associated with the formation of scar ...
(a disease characterized by increased numbers of senescent cells) given dasatinib and quercetin showed improved physical function and evidence of reduced senescent cells.


References


Further reading

* {{Authority control Aminopyrimidines Anilides Drugs developed by Bristol Myers Squibb Chloroarenes Non-receptor tyrosine kinase inhibitors Orphan drugs Otsuka Pharmaceutical 1-(2-Pyrimidinyl)piperazines Hydroxyethyl compounds Thiazoles World Health Organization essential medicines Wikipedia medicine articles ready to translate