Dasatinib

Structural formula
General
Non-proprietary name	Dasatinib
other names	N - (2-chloro-6-methylphenyl) -2 - ({6- [4- (2-hydroxyethyl) -1-piperazinyl] -2-methyl-4-pyrimidinyl} amino) -1,3-thiazole-5 -carboxamide ( IUPAC )
Molecular formula	C 22 H 26 ClN 7 O 2 S
External identifiers / databases
EC number	801-607-0
ECHA InfoCard	100.228.321
PubChem	3062316
ChemSpider	2323020
DrugBank	DB01254
Wikidata	Q419940
Drug information
ATC code	L01 XE06
Drug class	Cytostatic
Mechanism of action	Tyrosine kinase inhibitor
properties
Molar mass	488.01 g · mol -1
safety instructions
	Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
H and P phrases	H: 301-315-318-351-361-372-410
	P: ?
	As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Bioavailability	? %
Plasma protein binding	96%
metabolism	Hepatic
Plasma half-life	1.3 to 5 hours
Administration form	Orally
pregnancy	Careful risk-benefit assessment

Dasatinib (trade name: Sprycel ; manufacturer: Bristol-Myers Squibb ) is a protein kinase inhibitor from the group of tyrosine kinase inhibitors , which is used as a medicinal substance for the treatment of certain malignant diseases ( chronic myeloid leukemia (CML) and Philadelphia chromosome- positive acute lymphoblastic leukemia (Ph + ALL)).

pharmacology

Mode of action

Like the active ingredient imatinib , which was approved in 2001 , dasatinib is a specific tyrosine kinase inhibitor of BCR-ABL kinase and SRC kinase. However, dasatinib is still effective in 32 of 33 known mutations of the Philadelphia chromosome for which imatinib has no effect. Only the gene mutation T315I apparently prevents binding to the specific binding site of the tyrosine kinase .

Effectiveness study

In a phase 1 dose adjustment study published in June 2006 , dasatinib was tested in patients who showed resistance or intolerance to imatinib. A complete haematological remission was achieved in 37 of 40 patients in the chronic phase of CML . A clear response to blood values was achieved in 31 of 44 patients who were in the accelerated phase of CML or blast crisis or who had Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL). The current 24 month data (ASH abstract # 734) continues to show the high effectiveness of dasatinib. Dasatinib-induced cytogenetic response is permanent in patients with chronic phase CML (CP-CML) who are resistant to or cannot tolerate imatinib.

Duration of effectiveness

In 95% of the patients in the chronic phase , the efficacy lasted for a mean observation period of more than twelve months. Of the patients in the acceleration phase of the CML, 82% remained in remission during a mean observation period of 5 months . Almost all patients with the blast crisis of CML or with Ph + ALL relapsed within 6 months. The progression-free survival at 15 months was 90%, while overall survival was 96%. Dose interruptions were necessary in 87% of the patients and a dose reduction in 73%; the average daily dose administered was 101 mg (between 11 and 171 mg).

Side effects

Long-term effects and side effects of dasatinib are being investigated in ongoing studies. The following more common side effects are known: headache, diarrhea, nausea, fatigue, rashes, edema, shortness of breath, pleural effusions, fungal diseases and joint pain. Much less common are: loss of appetite, pneumonia and intestinal bleeding. The following are very rare: heart failure, cardiac arrhythmias, high blood pressure, pulmonary edema, surface edema, elevated liver and creatinine values and calcium deficiency. Reports of grade 3–4 platelet deficiency (thrombocytopenia) (severe and very severe side effect) and a decrease in the number of neutrophils in the blood (neutropenia) grade 3–4 were recorded in 48% and 49% of patients, respectively. Non-haematological side effects consisted mainly of diarrhea (37%), headache (32%), fatigue (31%) and shortness of breath (30%). 27% of patients experienced a pleural effusion (abnormal accumulation of fluid in the pleural cavity); which was classified as grade 1–2 in 21% and grade 3–4 in 6% of patients. In the course of pharmacovigilance , a connection between therapy with Sprycel ^® and the occurrence of high blood pressure in the pulmonary circulation ( pulmonary arterial hypertension , PAH) was established, so the manufacturer Bristol-Myers Squibb warned accordingly.

history

Dasatinib was developed by Bristol-Myers Squibb (BMS) under the project name BMS-354825. The non-proprietary name is derived from the name of one of the chemists involved in the synthesis at BMS, Jagabandhu Das. It has been approved as a medicinal substance in the USA since June 2006 and in the EU since November 2006 and is marketed under the trade name Sprycel . The application was initially on the treatment of adult patients with imatinib - resistance limited or intolerant (so-called second-line), the end of 2010 was admitted for the first-line treatment.

Web links

Dasatinib (Sprycel) approved in Europe for imatinib resistance . leukaemie-online.de, November 28, 2006
Information from the manufacturer on Sprycel / Dasatinib (English)

Individual evidence

↑ Template: CL Inventory / not harmonized There is not yet a harmonized classification for this substance . A labeling of N - (2-chloro-6-methylphenyl) -2 - ({6- [4- (2-hydroxyethyl) piperazin-1-yl] -2-methylpyrimidin-4-) is shown, which is derived from a self-classification by the distributor yl} amino) -1,3-thiazole-5-carboxamide in the Classification and Labeling Inventory of the European Chemicals Agency (ECHA), accessed on January 13, 2020.

↑ European Commission Approves Expanded Indication for Sprycel (dasatinib) to Include Treatment of Children with Philadelphia Chromosome-Positive Chronic Myeloid Leukemia in Chronic Phase PM BMS, July 5, 2018, accessed July 8, 2018

↑ Moshe Talpaz et al. (2006): Dasatinib in Imatinib-Resistant Philadelphia Chromosome – Positive Leukemias. (PDF) In: N Engl J Med. Volume 354, pp. 2531-2541, PMID 16775234 .

^ Red Hand Letter from Bristol-Myers Squibb on August 2nd, 2011. (PDF; 352 kB) Retrieved on August 4th, 2011 .

↑ Jagabandhu Das, Ping Chen, Derek Norris, Ramesh Padmanabha, James Lin, Robert V. Moquin, Zhongqi Shen, Lynda S. Cook, Arthur M. Doweyko, Sidney Pitt, Suhong Pang, Ding Ren Shen, Qiong Fang, Henry F. de Fex, Kim W. McIntyre, David J. Shuster, Kathleen M. Gillooly, Kamelia Behnia, Gary L. Schieven, John Wityak, Joel C. Barrish: 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. In: Journal of Medicinal Chemistry , 49, 2006, pp. 6819-6832, PMID 17154512 , doi: 10.1021 / jm060727j .

[1] Template: CL Inventory / not harmonized There is not yet a harmonized classification for this substance . A labeling of N - (2-chloro-6-methylphenyl) -2 - ({6- [4- (2-hydroxyethyl) piperazin-1-yl] -2-methylpyrimidin-4-) is shown, which is derived from a self-classification by the distributor yl} amino) -1,3-thiazole-5-carboxamide in the Classification and Labeling Inventory of the European Chemicals Agency (ECHA), accessed on January 13, 2020.

[2] European Commission Approves Expanded Indication for Sprycel (dasatinib) to Include Treatment of Children with Philadelphia Chromosome-Positive Chronic Myeloid Leukemia in Chronic Phase PM BMS, July 5, 2018, accessed July 8, 2018

[3] Moshe Talpaz et al. (2006): Dasatinib in Imatinib-Resistant Philadelphia Chromosome – Positive Leukemias. (PDF) In: N Engl J Med. Volume 354, pp. 2531-2541, PMID 16775234 .

[4] Red Hand Letter from Bristol-Myers Squibb on August 2nd, 2011. (PDF; 352 kB) Retrieved on August 4th, 2011 .

[5] Jagabandhu Das, Ping Chen, Derek Norris, Ramesh Padmanabha, James Lin, Robert V. Moquin, Zhongqi Shen, Lynda S. Cook, Arthur M. Doweyko, Sidney Pitt, Suhong Pang, Ding Ren Shen, Qiong Fang, Henry F. de Fex, Kim W. McIntyre, David J. Shuster, Kathleen M. Gillooly, Kamelia Behnia, Gary L. Schieven, John Wityak, Joel C. Barrish: 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. In: Journal of Medicinal Chemistry , 49, 2006, pp. 6819-6832, PMID 17154512 , doi: 10.1021 / jm060727j .