Dabrafenib

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Structural formula
Dabrafenib structural formula
General
Non-proprietary name Dabrafenib
other names

N - {3- [5- (2-Amino-4-pyrimidinyl) -2- (2-methyl-2-propanyl) -1,3-thiazol-4-yl] -2-fluorophenyl} -2,6- difluorobenzenesulfonamide

Molecular formula C 23 H 20 F 3 N 5 O 2 S 2
Brief description

white to slightly colored solid

External identifiers / databases
CAS number
  • 1195765-45-7
  • 1195768-06-9 (dabrafenib mesylate )
EC number 689-166-9
ECHA InfoCard 100.215.965
PubChem 44462760
ChemSpider 25948204
DrugBank DB08912
Wikidata Q3011604
Drug information
ATC code

L01 XE23

Drug class

Tyrosine kinase inhibitor

Mechanism of action

inhibits the B RAF kinase

properties
Molar mass 519.56 g mol −1
Physical state

firmly

density

1.443 g cm −3

solubility

Soluble in DMSO (30 mg / ml at 25 ° C), water (<1 mg / ml at 25 ° C), ethanol (<1 mg / ml at 25 ° C)

safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS hazard labeling
no classification available
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Dabrafenib (trade name: Tafinlar ; manufacturer: Novartis ) is a drug from the group of protein kinase inhibitors , resp. the MAP kinase inhibitor , which inhibits the function of the BRAF protein . Dabrafenib is used in adult patients to treat non - small cell lung cancer (NSCLC) and malignant melanoma when these tumors have a mutation in the BRAF gene and can no longer be completely removed by surgery.

properties

BRAF is a member of the RAF family, which belongs to the serine / threonine protein kinases . RAF proteins play a crucial role in the MAP kinase pathway , e.g. B. in the regulation of embryogenesis , cell differentiation , cell growth and programmed cell death . Since BRAF regulates transcription factors for cell growth and proliferation via the MAP kinase pathway, it often also acts as an oncogene. In malignant melanoma in particular, BRAF mutations are found in around 50 to 60% of patients, mostly at amino acid position 600, which simulate the phosphorylation of the BRAF kinase domain and thus constitutively activate the MAP kinase pathway. However, also with other cancers - such as B. in approx. 3% of non-small cell lung cancers - activating BRAF mutations occur. Dabrafenib acts as a kinase inhibitor that inhibits the signaling of the mutated BRAF protein and can thus limit the growth of the mutated cells.

Development and marketing

The drug dabrafenib was protected by the pharmaceutical company GlaxoSmithKline in 2009 and has been marketed by the latter since the oncology division was sold to Novartis in 2015 . Under the name Tafinlar , dabrafenib was approved for the oral treatment (capsules) of adult patients with unresectable or metastatic melanoma with BRAF-V600E mutations by the Food and Drug Administration in May 2013 for the US market and by the European Commission in August 2013 EU -wide approved. The combination of dabrafenib with the MEK inhibitor trametinib was first approved in the US in January 2014 and in the EU in September 2015. In April 2017, the EU approval of the combination of dabrafenib with trametinib was extended to include the treatment of adult patients with advanced non-small cell lung cancer with BRAF V600E mutations.

synthesis

The synthesis of dabrafenib is a six-step reaction. In the first step, 3-bromo-2-fluorobenzoic acid 1 is esterified with methanol under acid catalysis . The methyl 3-bromo-2-methylbenzoate 2 reacts with tert-butyl carbamate 3 in the presence of the complex compound of palladium with dibenzylidene acetone (Pd 2 (dba) 3 ) and Cs 2 CO 3 in the sense of a Buchwald-Hartwig coupling to form the 3-amino 2-methylbenzoic acid methyl ester 4 . The reaction of 4 with 2,6-difluorobenzenesulfonyl chloride 5 gives the sulfonamide 6 , which reacts with 2-chloro-4-methylpyrimidine 7 in the presence of LHMDS to form intermediate 8 . The N - [3- [2- (2-chloro-4-pyrimidinyl) acetyl], 2-fluorophenyl] -2,6-difluoro-benzenesulfonamide 8 cyclizes with 2,2-dimethylpropanthioamide 9 in the presence of NBS to give the thiazole 10 . Finally, the amino group is introduced into the end product 11 with ammonia in methanol .

Synthesis of dabrafenib

pharmacology

Mechanism of action

As an inhibitor of B Raf kinase, dabrafenib leads to a reduced activation of MEK1 / 2, which is phosphorylated and thus activated by Raf kinase under physiological conditions. Since MEK1 / 2 remains inactivated, it is again unable to phosphorylate the ERK 1/2 (isoforms of MAP-K) and thus continue the cascade. As a result, the transcription factors can no longer be phosphorylated by the MAP kinases and the transcription of a large number of target genes is aborted, which has an inhibitory effect on cell proliferation, cell growth and differentiation.

Dabrafenib inhibits some subgroups of the BRAF kinases with IC50 values ​​of BRAF V600E (0.65), BRAF V600K (0.5) and BRAF V600D (1.84) measured in vitro .

metabolism

Dabrafenib is metabolised in the liver via cytochrome P450 3A4 (CYP3A4) and cytochrome P450 2C8 . Hydroxy-dabrafenib is formed as a metabolite, which is then oxidized via CYP3A4 to carboxy-dabrafenib. Carboxy Dabrafenib either biliary or renal eliminated or decarboxylated to desmethyl Dabrafenib which is then reabsorbed by the intestines. Desmethyl-dabrafenib is then metabolised by CYP3A4.

interaction

The effect of dabrafenib can be reduced by CYP3A4-inducing drugs, since dabrafenib is metabolized precisely via this enzyme and its effective concentration is thereby reduced. These drugs include e.g. B. carbamazepine, phenobarbital or phenytoin. An increased level of dabrafenib could be caused by drugs that have an inhibitory effect on CYP3A4 / CYP2C8 metabolism. Examples of this would be: clarithromycin, gemfibrozil (CYP2C8 inhibitor), ketoconazole.

Side effects

Side effects include hyperkeratosis , pyrexia , headache, dizziness, arthralgia , hair loss, papilloma and hand-foot syndrome .

Clinical study

In a phase 3 study, patients with advanced metastatic melanoma and a proven BRAF V600 mutation were treated with dabrafenib or dacarbazine, which was used as the standard therapy for this disease. It was found that treatment with dabrafenib reduced disease progression by 70% compared to standard therapy with dacarbazine. The progression-free survival rate ( PFS ) was 5.1 months for dabrafenib and 2.7 months for dacarbazine . The overall response rate was 50% with dabrafenib and 6% with dacarbazine.

Early benefit assessment according to § 35a SGB V

For adults with BRAF V600 mutation-positive, unresectable or metastatic melanoma , the IQWiG saw an added benefit of dabrafenib as monotherapy compared to the appropriate comparator therapy because of only minor positive effects and the lack of informative value of the study data on possible negative effects Dacarbazine as not used. The Federal Joint Committee (G-BA) endorsed the assessment. In 2016, he lifted an initially set time limit for his decision.

For the combination with trametinib , the IQWiG saw an indication of a considerable added benefit in women and an indication of a considerable added benefit for men in the same indication. The G-BA did not differentiate according to gender and overall gave the combination an indication of a considerable additional benefit.

In its assessment of the active ingredient combination for the adjuvant treatment of adults with stage III melanoma with a proven BRAF V600 mutation after complete resection with metastasectomy, the IQWiG recognized an indication of a considerable additional benefit. The G-BA agreed with this in its decision.

In its assessment of dabrafenib in combination with trametinib for the treatment of adults with advanced non-small cell lung cancer with a BRAF V600 mutation , the IQWiG in 2017 came to the conclusion that, in the absence of suitable study data, there was no added benefit over the respective appropriate comparator therapy either in the first line or for previously treated patients is occupied. The G-BA agreed with the assessment result.

toxicology

Dabrafenib has not been shown to be mutagenic or clastogenic in vitro in bacteria and mammalian cell cultures and in vivo in the micronucleus test in rodents . Carcinogenicity studies with dabrafenib have not been conducted.

In combined studies of female fertility and early embryonic and embryofetal development in rats, the number of corpora lutea in the ovaries of pregnant females was reduced at 300 mg / kg / day ( approximately three times the clinical exposure in humans based on AUC ) However, no effects on the cycle, mating behavior or fertility could be determined. Developmental toxic phenomena, e.g. B. Embryo mortality and ventricular septal defects were observed at doses of 300 mg / kg / day, delayed skeletal development and reduced fetal weight from doses of 20 mg / kg / day (based on the AUC, corresponds to more than 0.5 times the clinical exposure observed in humans. Male fertility studies have not been conducted with dabrafenib. However, testicular degeneration / atrophy was observed in the rat and dog in repeated dose studies (at doses in excess of 0.2 times the human clinical exposure based on AUC). The testicular changes in the rat and the dog were still present after a four-week recovery period.

literature

  • Ernst Mutschler et al .: Mutschler - drug effects textbook of pharmacology and toxicology . 10th edition. Scientific Verlagsgesellschaft, Stuttgart 2012, ISBN 3-8047-2898-7 .

Individual evidence

  1. ↑ European Medicines Agency: Dabrafenib Public Assessment Report (PDF) .
  2. ↑ data sheet scbio .
  3. ↑ This substance has either not yet been classified with regard to its hazardousness or a reliable and citable source has not yet been found.
  4. ↑ T. Huang, M. Karsy, J. Zhuge, M. Zhong, D. Liu: B-Raf and the inhibitors: from bench to bedside. In: Journal of Hematology & Oncology . Volume 6, 2013, p. 30, doi : 10.1186 / 1756-8722-6-30 , PMID 23617957 , PMC 3646677 (free full text).
  5. ↑ Dabrafenib (Tafinlar) in black skin cancer , from www.gesundheitsinformation.de, accessed on August 6, 2018
  6. ↑ MM Machnicki, T. Stoklosa: BRAF - A new player in hematological neoplasms. In: Blood cells, molecules & diseases. [electronic publication before printing] February 2014, doi : 10.1016 / j.bcmd.2014.01.001 , PMID 24495477 .
  7. ^ A b S. McGettigan: Dabrafenib: A New Therapy for Use in BRAF-Mutated Metastatic Melanoma. In: Journal of the advanced practitioner in oncology. Volume 5, number 3, May 2014, pp. 211-215, PMID 25089220 , PMC 4114496 (free full text) (review).
  8. ↑ a b J. J. Luke, PA Ott: New developments in the treatment of metastatic melanoma - role of dabrafenib-trametinib combination therapy. In: Drug, healthcare and patient safety. Volume 6, 2014, pp. 77-88, doi : 10.2147 / DHPS.S39568 , PMID 25018652 , PMC 4075957 (free full text) (review).
  9. ↑ Dong Chen, Li-Qun Zhang, Jun-Fu Huang, Kai Liu, Zheng-Ran Chuai: BRAF mutations in patients with non-small cell lung cancer: a systematic review and meta-analysis. In: PloS One . tape 9 , no. 6 , June 30, 2014, doi : 10.1371 / journal.pone.0101354 , PMID 24979348 , PMC 4076330 (free full text).
  10. ↑ Novartis Announces Closing of Transactions with GSK. (No longer available online.) Novartis March 2, 2015, archived from the original on May 1, 2016 ; accessed on May 2, 2016 . Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. @1@ 2Template: Webachiv / IABot / www.novartis.ch
  11. ↑ Tafinlar-Dabrafenib , European public assessment report (EPAR), accessed on April 28, 2014
  12. ↑ AJ King, MR Arnone, MR Bleam, KG Moss, J. Yang, KE Fedorowicz, KN Smitheman, JA Erhardt, A. Hughes-Earle, LS Kane-Carson, RH Sinnamon, H. Qi, TR Rheault, DE Uehling, SG Laquerre: dabrafenib; preclinical characterization, increased efficacy when combined with trametinib, while BRAF / MEK tool combination reduced skin lesions. In: PLoS ONE . Volume 8, number 7, 2013, p. E67583, doi : 10.1371 / journal.pone.0067583 , PMID 23844038 , PMC 3701070 (free full text).
  13. ^ AK Salama, KB Kim: Trametinib (GSK1120212) in the treatment of melanoma. In: Expert Opinion on Pharmacotherapy . Volume 14, Number 5, April 2013, pp. 619-627, doi : 10.1517 / 14656566.2013.770475 , PMID 23432625 .
  14. ↑ Silas Inman: Dabrafenib / Trametinib Combination Approved for Advanced Melanoma , OncLive, January 9, 2014
  15. ↑ Novartis receives EU approval for Tafinlar® and Mekinist®, first combination approved for patients with aggressive form of melanoma ( Memento des Originals dated December 22, 2015 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. , Novartis press release of September 1, 2015. @1@ 2Template: Webachiv / IABot / www.novartis.com
  16. ^ Tara R. Rheault, John C. Stellwagen, George M. Adjabeng: Discovery of Dabrafenib: A Selective Inhibitor of Raf Kinases with Antitumor Activity against B-Raf-Driven Tumors. In: American Chemical Society Med. Chem. Lett. 4, No. 3, 2013, pp. 358-362, doi : 10.1021 / ml4000063 .
  17. ↑ Summary Basis of Decision (SBD): Tafinlar - 2013 - Health Canada ( Memento of the original dated February 8, 2014 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice.  @1@ 2Template: Webachiv / IABot / www.hc-sc.gc.ca
  18. ↑ a b c Entry on dabrafenib in the DrugBank of the University of Alberta , accessed November 18, 2019.
  19. ↑ patent
  20. ↑ a b Tafinlar summary
  21. ↑ Medicines commission  ( page no longer available , search in web archives )  Info: The link was automatically marked as defective. Please check the link according to the instructions and then remove this notice.@1@ 2Template: Toter Link / www.sindbad-mds.de  
  22. ^ A. Hauschild, JJ Grob, LV Demidov, T. Jouary, R. Gutzmer, M. Millward, P. Rutkowski, CU Blank, WH Miller, E. Kaempgen, S. Martín-Algarra, B. Karaszewska, C. Mauch , V. Chiarion-Sileni, AM Martin, S. Swann, P. Haney, B. Mirakhur, ME Guckert, V. Goodman, PB Chapman: Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomized controlled trial. In: Lancet. Volume 380, Number 9839, July 2012, pp. 358-365, doi : 10.1016 / S0140-6736 (12) 60868-X , PMID 22735384 .
  23. ↑ A13-35 Dabrafenib - Benefit assessment according to Section 35a SGB V , accessed on July 8, 2019.
  24. ↑ A14-10 Addendum to Commission A13-35 (Dabrafenib) - Benefit assessment according to Section 35a SGB V , accessed on July 8, 2019.
  25. ↑ - Resolutions of the Federal Joint Committee of April 3, 2014 and June 16, 2016 on the benefit assessment procedure for the active ingredient dabrafenib , accessed on July 7, 2019.
  26. ↑ A15-39 Dabrafenib (melanoma) - Benefit assessment according to Section 35a SGB V , accessed on July 8, 2019.
  27. ↑ A16-05 Dabrafenib / Trametinib - Addendum to Commission A15-39 and A15-40 , accessed on July 8, 2019.
  28. ↑ Resolution of the Federal Joint Committee of March 17, 2016 on the benefit assessment procedure for the active ingredient dabrafenib (new area of ​​application: melanoma in combination with trametinib) , accessed on July 8, 2019.
  29. ↑ A18-59 Dabrafenib (melanoma) - Benefit assessment according to Section 35a SGB V , accessed on July 8, 2019.
  30. ↑ Resolution of the Federal Joint Committee of March 22, 2019 on the benefit assessment procedure for the active ingredient dabrafenib (new area of ​​application: melanoma, in combination with trametinib, BRAF V600 mutation, adjuvant therapy) , accessed on July 8, 2019.
  31. ↑ See also Patrick Terheyden, Angela Krackhardt, Thomas Eigenler: Systemtherapie des Melanom. Use of immune checkpoint inhibitors and inhibition of intracellular signal transduction. In: Deutsches Ärzteblatt. Volume 116, issue 29 f., (July 22) 2019, pp. 497-504, especially p. 504.
  32. ↑ A17-17 Dabrafenib (non-small cell lung carcinoma) - benefit assessment according to Section 35a SGB V , accessed on September 6, 2018.
  33. ↑ Resolution of the Federal Joint Committee of October 19, 2017 on an amendment to the Drugs Directive (AM-RL): Annex XII - Dabrafenib (new area of ​​application: non-small cell lung cancer) , accessed on September 6, 2018.