Dasatinib

Last updated

Dasatinib
Dasatinib.svg
Dasatinib-2GQG-ball-and-stick-flip.png
Clinical data
Trade names Sprycel, Dasanix
AHFS/Drugs.com Monograph
MedlinePlus a607063
License data
Pregnancy
category
  • AU:D
Routes of
administration 		By mouth (tablets)
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only) [1]
  • UK: POM (Prescription only)
  • US: ℞-only
  • EU:Rx-only [2]
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Protein binding 96%
Metabolism Liver
Elimination half-life 1.3 to 5 hours
Excretion Fecal (85%), kidney (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
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.228.321 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C22H26ClN7O2S
Molar mass 488.01 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) Yes check.svgY
  • Key:ZBNZXTGUTAYRHI-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Dasatinib, sold under the brand name Sprycel among others, is a targeted therapy medication used to treat certain cases of chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL). [3] Specifically it is used to treat cases that are Philadelphia chromosome-positive (Ph+). [3] It is taken by mouth. [3]

Contents

Common adverse effects include low white blood cells, low blood platelets, anemia, swelling, rash, and diarrhea. [3] Severe adverse effects may include bleeding, pulmonary edema, heart failure, and prolonged QT syndrome. [3] Use during pregnancy may result in harm to the baby. [3] It is a tyrosine-kinase inhibitor and works by blocking a number of tyrosine kinases such as Bcr-Abl and the Src kinase family. [3]

Dasatinib was approved for medical use in the United States and in the European Union in 2006. [3] [2] It is on the World Health Organization's List of Essential Medicines. [4]

Medical uses

Dasatinib is used to treat people with chronic myeloid leukemia and people with acute lymphoblastic leukemia who are positive for the Philadelphia chromosome. [5]

In the EU dasatinib is indicated for children with

and adults with

Adverse effects

The most common side effects are infection, suppression of the bone marrow (decreasing numbers of leukocytes, erythrocytes, and thrombocytes), [6] headache, hemorrhage (bleeding), pleural effusion (fluid around the lungs), dyspnea (difficulty breathing), diarrhea, vomiting, nausea (feeling sick), abdominal pain (belly ache), skin rash, musculoskeletal pain, tiredness, swelling in the legs and arms and in the face, fever. [2] Neutropenia and myelosuppression were common toxic effects. Fifteen people (of 84, i.e. 18%) in the above-mentioned study developed pleural effusions, which was a suspected side effect of dasatinib. Some of these people required thoracentesis or pleurodesis to treat the effusions. Other adverse events included mild to moderate diarrhea, peripheral edema, and headache. A small number of people 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 people treated with dasatinib, [7] possibly due to pulmonary endothelial cell damage. [8]

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). [9] Symptoms of PAH may include shortness of breath, fatigue, and swelling of the body (such as the ankles and legs). [9] In reported cases, people developed PAH after starting dasatinib, including after more than one year of treatment. [9] Information about the risk was added to the Warnings and Precautions section of the Sprycel drug label. [9] 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. [10] Reported dasatinib-induced PAH had improvements after cessation of drug treatment. [10]

Pharmacology

Crystal structure (PDB 2GQG) of Abl kinase domain (blue) in complex with dasatinib (red). 2GQG Abl1Kinase Dasatinib.png
Crystal structure (PDB 2GQG) of Abl kinase domain (blue) in complex with dasatinib (red).

Dasatinib is an ATP-competitive protein tyrosine kinase inhibitor. The main targets of dasatinib are BCR/Abl (the "Philadelphia chromosome"), Src, c-Kit, ephrin receptors, and several other tyrosine kinases. [12] Strong inhibition of the activated BCR-ABL kinase distinguishes dasatinib from other CML treatments, such as imatinib and nilotinib. [12] [13] Although dasatinib only has a plasma half-life of three to five hours, the strong binding to BCR-ABL1 results in a longer duration of action. [13]

History

Dasatinib was developed by collaboration of Bristol-Myers Squibb and Otsuka Pharmaceutical Co., Ltd, [14] [15] [16] 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 chemists' underlying assumptions at a time when progress in the development of the molecule had stalled. [17]

Society and culture

Dasatinib was approved for used in the United States in June 2006 and in the European Union in November 2006 [18] [2]

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). [19]

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. [20]

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. [20] 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. [20] The majority of participants were treated with dasatinib tablets 60 mg/m2 body surface area once daily. [20] Participants were treated until disease progression or unacceptable toxicity. [20]

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. [21]

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. [21]

The Union for Affordable Cancer Treatment said that "the dasatinib dispute illustrates the shortcomings of US trade policy and its impact on cancer patients" [21]

Brand names

In Bangladesh dasatinib is available under the trade name Dasanix by Beacon Pharmaceuticals. [22] In India, It is marketed under the brand name Nextki by Emcure Pharmaceuticals.[ medical citation needed ]

Research

Dasatinib has been shown to eliminate senescent cells in cultured adipocyte progenitor cells. [23]

Dasatinib+Quercetin

Dasatinib has been shown to induce apoptosis in senescent cells by inhibiting Src kinase, whereas quercetin inhibits the anti-apoptotic protein Bcl-xL. [23] Administration of dasatinib along with quercetin to mice improved cardiovascular function and eliminated senescent cells. [24] Aged mice given dasatinib with quercetin showed improved health and survival. [24]

A study of fourteen human patients with idiopathic pulmonary fibrosis (a disease characterized by increased numbers of senescent cells) given dasatinib and quercetin showed improved physical function and evidence of reduced senescent cells. [23]

Related Research Articles

<span class="mw-page-title-main">Leukemia</span> Blood cancers forming in the bone marrow

Leukemia is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called blasts or leukemia cells. Symptoms may include bleeding and bruising, bone pain, fatigue, fever, and an increased risk of infections. These symptoms occur due to a lack of normal blood cells. Diagnosis is typically made by blood tests or bone marrow biopsy.

<span class="mw-page-title-main">Philadelphia chromosome</span> Genetic abnormality in leukemia cancer cells

The Philadelphia chromosome or Philadelphia translocation (Ph) is a specific genetic abnormality in chromosome 22 of leukemia cancer cells. This chromosome is defective and unusually short because of reciprocal translocation, t(9;22)(q34;q11), of genetic material between chromosome 9 and chromosome 22, and contains a fusion gene called BCR-ABL1. This gene is the ABL1 gene of chromosome 9 juxtaposed onto the breakpoint cluster region BCR gene of chromosome 22, coding for a hybrid protein: a tyrosine kinase signaling protein that is "always on", causing the cell to divide uncontrollably by interrupting the stability of the genome and impairing various signaling pathways governing the cell cycle.

<span class="mw-page-title-main">Chronic myelogenous leukemia</span> Medical condition

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 accumulation of these cells in the blood. CML is a clonal bone marrow stem cell disorder in which a proliferation of mature granulocytes and their precursors is found. It is a type of myeloproliferative neoplasm associated with a characteristic chromosomal translocation called the Philadelphia chromosome.

<span class="mw-page-title-main">Imatinib</span> Chemical compound

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 such as CSF1R, ABL, c-KIT, FLT3, and PDGFR-β. Specifically, it is used for chronic myelogenous leukemia (CML) and acute lymphocytic leukemia (ALL) that are Philadelphia chromosome–positive (Ph+), certain types of gastrointestinal stromal tumors (GIST), hypereosinophilic syndrome (HES), chronic eosinophilic leukemia (CEL), systemic mastocytosis, and myelodysplastic syndrome.

<span class="mw-page-title-main">Acute lymphoblastic leukemia</span> Blood cancer characterised by overproduction of lymphoblasts

Acute lymphoblastic leukemia (ALL) is a cancer of the lymphoid line of blood cells characterized by the development of large numbers of immature lymphocytes. Symptoms may include feeling tired, pale skin color, fever, easy bleeding or bruising, enlarged lymph nodes, or bone pain. As an acute leukemia, ALL progresses rapidly and is typically fatal within weeks or months if left untreated.

<span class="mw-page-title-main">Nilotinib</span> Chemical compound

Nilotinib, sold under the brand name Tasigna marketed worldwide by Novartis, is a 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 as in accelerated and chronic phase CML that has not responded to imatinib. It is taken by mouth.

Biphenotypic acute leukaemia (BAL) is an uncommon type of leukemia which arises in multipotent progenitor cells which have the ability to differentiate into both myeloid and lymphoid lineages. It is a subtype of "leukemia of ambiguous lineage".

<span class="mw-page-title-main">Bosutinib</span> Chemical compound

Bosutinib, sold under the brand name Bosulif, is a small molecule BCR-ABL and src tyrosine kinase inhibitor used for the treatment of chronic myelogenous leukemia.

<span class="mw-page-title-main">ARIAD Pharmaceuticals</span> Defunct oncology company

ARIAD Pharmaceuticals, Inc. was an American oncology company, now part of Takeda Oncology, which was founded in 1991 by Harvey J. Berger, M.D. and headquartered in Cambridge, Massachusetts. ARIAD engaged in the discovery, development, and commercialization of medicines for cancer patients.

<span class="mw-page-title-main">Omacetaxine mepesuccinate</span> Chemical compound

Omacetaxine mepesuccinate, formerly named as homoharringtonine or HHT, is a pharmaceutical drug substance that is indicated for treatment of chronic myeloid leukemia (CML).

<span class="mw-page-title-main">Nicholas Lydon</span> British biochemist

Nicholas B. Lydon FRS is a British scientist and entrepreneur. In 2009, he was awarded the Lasker Clinical Award and in 2012 the Japan Prize for the development of Gleevec, also known as Imatinib, a selective BCR-ABL inhibitor for the treatment of chronic myeloid leukaemia (CML), which converted a fatal cancer into a manageable chronic condition.

<span class="mw-page-title-main">Tyrosine kinase inhibitor</span> Drug typically used in cancer treatment

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 phosphate group to the protein (phosphorylation), a step that TKIs inhibit. TKIs are typically used as anticancer drugs. For example, they have substantially improved outcomes in chronic myelogenous leukemia. They have also been used to treat other diseases, such as idiopathic pulmonary fibrosis.

Bcr-Abl tyrosine-kinase inhibitors (TKI) are the first-line therapy for most patients with chronic myelogenous leukemia (CML). More than 90% of CML cases are caused by a chromosomal abnormality that results in the formation of a so-called Philadelphia chromosome. This abnormality was discovered by Peter Nowell in 1960 and is a consequence of fusion between the Abelson (Abl) tyrosine kinase gene at chromosome 9 and the break point cluster (Bcr) gene at chromosome 22, resulting in a chimeric oncogene (Bcr-Abl) and a constitutively active Bcr-Abl tyrosine kinase that has been implicated in the pathogenesis of CML. Compounds have been developed to selectively inhibit the tyrosine kinase.

<span class="mw-page-title-main">Ponatinib</span> Oral drug

Ponatinib, sold under the brand name Iclusig, is a medication developed by ARIAD Pharmaceuticals for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL). It is a multi-targeted tyrosine-kinase inhibitor. Some forms of CML, those that have the T315I mutation, are resistant to current therapies such as imatinib. Ponatinib has been designed to be effective against these types of tumors.

Atypical chronic myeloid leukemia (aCML) is a type of leukemia. It is a heterogeneous disorder belonging to the group of myelodysplastic/myeloproliferative (MDS/MPN) syndromes.

<span class="mw-page-title-main">Radotinib</span> Chemical compound

Radotinib (INN; trade name Supect), and sometimes referred to by its investigational name IY5511, is a drug for the treatment of different types of cancer, most notably Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) with resistance or intolerance of other Bcr-Abl tyrosine-kinase inhibitors, such as patients resistant or intolerant to imatinib.

<span class="mw-page-title-main">Bafetinib</span> Chemical compound

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<span class="mw-page-title-main">Asciminib</span> Chemical compound

Asciminib, sold under the brand name Scemblix, is a medication used to treat Philadelphia chromosome-positive chronic myeloid leukemia. Asciminib is a protein kinase inhibitor.

References

  1. ↑ "Sprycel (Dasatinib)" (PDF). Therapeutic Goods Administration (TGA). Retrieved 18 July 2020.
  2. 1 2 3 4 5 6 7 8 9 10 "Sprycel EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 28 April 2020.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  3. 1 2 3 4 5 6 7 8 "Dasatinib". The American Society of Health-System Pharmacists. Retrieved 8 December 2017.
  4. ↑ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl: 10665/325771 . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  5. ↑ Keating GM (January 2017). "Dasatinib: A Review in Chronic Myeloid Leukaemia and Ph+ Acute Lymphoblastic Leukaemia". Drugs. 77 (1): 85–96. doi:10.1007/s40265-016-0677-x. PMID   28032244. S2CID   207489056.
  6. ↑ Olivieri A, Manzione L (June 2007). "Dasatinib: a new step in molecular target therapy". Annals of Oncology. 18 (Suppl 6): vi42–vi46. doi: 10.1093/annonc/mdm223 . PMID   17591830.
  7. ↑ "NHS - Healthcare News". nelm.nhs.uk. Archived from the original on 5 May 2013. Retrieved 27 September 2011.
  8. ↑ Yurttaş NO, Eşkazan AE (2018). "Dasatinib-induced pulmonary arterial hypertension". British Journal of Clinical Pharmacology . 84 (5): 835–845. doi:10.1111/bcp.13508. PMC   5903230 . PMID   29334406.
  9. 1 2 3 4 "Sprycel (dasatinib) and risk of pulmonary arterial hypertension". U.S. Food and Drug Administration (FDA). 23 September 2011. Retrieved 28 April 2020.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  10. 1 2 Özgür Yurttaş N, Eşkazan AE (May 2018). "Dasatinib-induced pulmonary arterial hypertension". British Journal of Clinical Pharmacology. Wiley. 84 (5): 835–845. doi:10.1111/bcp.13508. PMC   5903230 . PMID   29334406.
  11. ↑ Tokarski JS, Newitt JA, Chang CY, Cheng JD, Wittekind M, Kiefer SE, et al. (June 2006). "The structure of Dasatinib (BMS-354825) bound to activated ABL kinase domain elucidates its inhibitory activity against imatinib-resistant ABL mutants". Cancer Research. 66 (11): 5790–7. doi: 10.1158/0008-5472.CAN-05-4187 . PMID   16740718.
  12. 1 2 Piscitani L, Sirolli V, Morroni M, Bonomini M (2020). "Nephrotoxicity Associated with Novel Anticancer Agents (Aflibercept, Dasatinib, Nivolumab): Case Series and Nephrological Considerations". International Journal of Molecular Sciences . 21 (14): e4878. doi: 10.3390/ijms21144878 . PMC   7402330 . PMID   32664269.
  13. 1 2 Braun TP, Eide CA, Druker BJ (2020). "Response and Resistance to BCR-ABL1-Targeted Therapies". Cancer Cell . 37 (4): 530–542. doi:10.1016/j.ccell.2020.03.006. PMC   7722523 . PMID   32289275.
  14. ↑ "Otsuka and Bristol-Myers Squibb Announce a Change in Contract Regarding Collaboration in Japan in the Oncology Therapy Area".
  15. ↑ "FDA Approves U.S. Product Labeling Update for Sprycel (dasatinib) to Include Three-Year First-Line and Five-Year Second-Line Efficacy and Safety Data in Chronic Myeloid Leukemia in Chronic Phase". Bristol-Myers Squibb (Press release). Archived from the original on 20 September 2018. Retrieved 23 April 2015.
  16. ↑ "Bristol-Myers Squibb Announces Extension of U.S. Agreement for ABILIFY and Establishment of an Oncology Collaboration with Otsuka". Bristol-Myers Squibb (Press release). Archived from the original on 31 January 2015.
  17. ↑ Drahl C (16 January 2012). "How Jagabandhu Das made dasatinib possible". The Safety Zone blog. Chemical & Engineering News. Archived from the original on 10 December 2017. Retrieved 29 August 2016.
  18. ↑ "Drug Approval Package: Sprycel (Dasatinib) NDA #021986 & 022072". U.S. Food and Drug Administration (FDA). 6 September 2006. Retrieved 28 April 2020.
  19. ↑ "2010 Notifications". U.S. Food and Drug Administration (FDA). 18 November 2010. Retrieved 28 April 2020.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  20. 1 2 3 4 5 "FDA approves dasatinib for pediatric patients with CML". U.S. Food and Drug Administration (FDA). 9 November 2017. Retrieved 28 April 2020.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  21. 1 2 3 Cohen D (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. PMID   25370846. S2CID   206903723.
  22. ↑ "Dasanix". Medex. Retrieved 19 May 2021.
  23. 1 2 3 Kirkland JL, Tchkonia T (2020). "Senolytic drugs: from discovery to translation". Journal of Internal Medicine . 288 (5): 518–536. doi:10.1111/joim.13141. PMC   7405395 . PMID   32686219.
  24. 1 2 Paez-Ribes M, González-Gualda E, Doherty GJ, Muñoz-Espín D (2019). "Targeting senescent cells in translational medicine". EMBO Molecular Medicine . 11 (12): e10234. doi:10.15252/emmm.201810234. PMC   6895604 . PMID   31746100.

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