Dasatinib,sold under the brand nameSprycelamong others, is atargeted therapymedication used to treat certain cases ofchronic myelogenous leukemia(CML) andacute lymphoblastic leukemia(ALL).[3]Specifically it is used to treat cases that arePhiladelphia chromosome-positive (Ph+).[3]It is takenby mouth.[3]
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| Trade names | Sprycel, Dasanix |
| AHFS/Drugs | Monograph |
| MedlinePlus | a607063 |
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| Routes of administration | By mouth(tablets) |
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| Pharmacokineticdata | |
| Protein binding | 96% |
| Metabolism | Liver |
| Eliminationhalf-life | 1.3 to 5 hours |
| Excretion | Fecal (85%),kidney(4%) |
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| ECHA InfoCard | 100.228.321 |
| Chemical and physical data | |
| Formula | C22H26ClN7O2S |
| Molar mass | 488.01g·mol−1 |
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Commonadverse effectsincludelow white blood cells,low blood platelets,anemia,swelling,rash, and diarrhea.[3]Severe adverse effects may include bleeding,pulmonary edema,heart failure,andprolonged QT syndrome.[3]Use duringpregnancymay result in harm to the baby.[3]It is atyrosine-kinase inhibitorand works by blocking a number oftyrosine kinasessuch asBcr-Abland theSrc 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 theWorld Health Organization's List of Essential Medicines.[4]
Medical uses
editDasatinib is used to treat people withchronic myeloid leukemiaand people withacute lymphoblastic leukemiawho are positive for thePhiladelphia chromosome.[5]
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.[2]
- newly diagnosed Ph+ acute lymphoblastic leukaemia (ALL) in combination with chemotherapy.[2]
- newly diagnosed Ph+ CML in chronic phase (Ph+ CML-CP) or Ph+ CML-CP resistant or intolerant to prior therapy including imatinib.[2]
and adults with
- newly diagnosed Philadelphia-chromosome-positive (Ph+) chronic myelogenous leukaemia (CML) in the chronic phase;[2]
- chronic, accelerated or blast phase CML with resistance or intolerance to prior therapy including imatinib mesilate;[2]
- Ph+ acute lymphoblastic leukaemia (ALL) and lymphoid blast CML with resistance or intolerance to prior therapy.[2]
Adverse effects
editThe most common side effects areinfection,suppression of the bone marrow(decreasing numbers ofleukocytes,erythrocytes,andthrombocytes),[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]Neutropeniaandmyelosuppressionwere common toxic effects. Fifteen people (of 84, i.e. 18%) in the above-mentioned study developedpleural effusions,which was a suspected side effect of dasatinib. Some of these people requiredthoracentesisorpleurodesisto treat the effusions. Other adverse events included mild to moderate diarrhea, peripheraledema,andheadache.A small number of people developed abnormalliver function testswhich returned to normal without dose adjustments. Mildhypocalcemiawas also noted, but did not appear to cause any significant problems. Several cases ofpulmonary arterial hypertension(PAH) were found in people treated with dasatinib,[7]possibly due to pulmonaryendothelial celldamage.[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
edit
Dasatinib is an ATP-competitive proteintyrosine kinase inhibitor.The main targets of dasatinib areBCR/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 asimatinibandnilotinib.[12][13]Although dasatinib only has aplasma half-lifeof three to five hours, the strong binding to BCR-ABL1 results in a longer duration of action.[13]
History
editDasatinib was developed by collaboration ofBristol-Myers Squibband 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 themedicinal chemists' underlying assumptions at a time when progress in the development of the molecule had stalled.[17]
Society and culture
editLegal status
editDasatinib 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/m2body surface areaonce daily.[20]Participants were treated until disease progression or unacceptable toxicity.[20]
Economics
editThe 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
editInBangladeshdasatinib is available under the trade name Dasanix byBeacon Pharmaceuticals.[22]In India, It is marketed under the brand name Nextki by Emcure Pharmaceuticals.[medical citation needed]
Research
editDasatinib has been shown to eliminatesenescent cellsin culturedadipocyte progenitor cells.[23]
Dasatinib+Quercetin
editDasatinib has been shown to induce apoptosis in senescent cells byinhibiting Src kinase,whereasquercetininhibits the anti-apoptotic proteinBcl-xL.[23]Administration of dasatinib along with quercetin to mice improvedcardiovascularfunction and eliminated senescent cells.[24]Aged mice given dasatinib with quercetin showed improved health and survival.[24]
A study of fourteen human patients withidiopathic 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]
References
edit- ^"Sprycel (Dasatinib)"(PDF).Therapeutic Goods Administration(TGA).Retrieved18 July2020.
- ^abcdefghij"Sprycel EPAR".European Medicines Agency(EMA).17 September 2018.Retrieved28 April2020.
This article incorporates text from this source, which is in thepublic domain.
- ^abcdefgh"Dasatinib".The American Society of Health-System Pharmacists.Retrieved8 December2017.
- ^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.
- ^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.PMID28032244.S2CID207489056.
- ^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.PMID17591830.
- ^"NHS - Healthcare News".nelm.nhs.uk.Archived fromthe originalon 5 May 2013.Retrieved27 September2011.
- ^Yurttaş NO, Eşkazan AE (2018)."Dasatinib-induced pulmonary arterial hypertension".British Journal of Clinical Pharmacology.84(5):835–845.doi:10.1111/bcp.13508.PMC5903230.PMID29334406.
- ^abcd"Sprycel (dasatinib) and risk of pulmonary arterial hypertension".U.S.Food and Drug Administration(FDA).23 September 2011.Retrieved28 April2020.This article incorporates text from this source, which is in thepublic domain.
- ^abÖzgür Yurttaş N, Eşkazan AE (May 2018)."Dasatinib-induced pulmonary arterial hypertension".British Journal of Clinical Pharmacology.84(5). Wiley:835–845.doi:10.1111/bcp.13508.PMC5903230.PMID29334406.
- ^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.PMID16740718.
- ^abPiscitani 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.PMC7402330.PMID32664269.
- ^abBraun 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.PMC7722523.PMID32289275.
- ^"Otsuka and Bristol-Myers Squibb Announce a Change in Contract Regarding Collaboration in Japan in the Oncology Therapy Area".17 April 2023.
- ^"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 fromthe originalon 20 September 2018.Retrieved23 April2015.
- ^"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 fromthe originalon 31 January 2015.
- ^Drahl C (16 January 2012)."How Jagabandhu Das made dasatinib possible".The Safety Zone blog.Chemical & Engineering News.Archived fromthe originalon 10 December 2017.Retrieved29 August2016.
- ^"Drug Approval Package: Sprycel (Dasatinib) NDA #021986 & 022072".U.S.Food and Drug Administration(FDA).6 September 2006.Retrieved28 April2020.
- ^"2010 Notifications".U.S.Food and Drug Administration(FDA).18 November 2010.Retrieved28 April2020.This article incorporates text from this source, which is in thepublic domain.
- ^abcde"FDA approves dasatinib for pediatric patients with CML".U.S.Food and Drug Administration(FDA).9 November 2017.Retrieved28 April2020.This article incorporates text from this source, which is in thepublic domain.
- ^abcCohen 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.PMID25370846.S2CID206903723.
- ^"Dasanix".Medex.Retrieved19 May2021.
- ^abcKirkland JL, Tchkonia T (2020)."Senolytic drugs: from discovery to translation".Journal of Internal Medicine.288(5):518–536.doi:10.1111/joim.13141.PMC7405395.PMID32686219.
- ^abPaez-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.PMC6895604.PMID31746100.
Further reading
edit- Lombardo LJ, Lee FY, Chen P, Norris D, Barrish JC, Behnia K, et al. (December 2004). "Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays".Journal of Medicinal Chemistry.47(27):6658–61.doi:10.1021/jm049486a.PMID15615512.
External links
edit- "Dasatinib".Drug Information Portal.U.S. National Library of Medicine.
