Fexinidazole

Fexinidazole is a medication used to treat African trypanosomiasis (sleeping sickness) caused by Trypanosoma brucei gambiense.[3] It is effective against both first and second stage disease.[3] Some evidence also supports its use in Chagas disease.[4] It is taken by mouth.[4]

Fexinidazole
Clinical data
Other names
  • Fexinidazole Winthrop
  • HOE 239
License data
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Identifiers
IUPAC name
  • 1-Methyl-2-{[4-(methylsulfanyl)phenoxy]methyl}-5-nitro-1H-imidazole
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.207.619
Chemical and physical data
FormulaC12H13N3O3S
Molar mass279.31 g·mol−1
3D model (JSmol)
SMILES
  • [O-][N+](=O)c1cnc(n1C)COc2ccc(SC)cc2
InChI
  • InChI=1S/C12H13N3O3S/c1-14-11(13-7-12(14)15(16)17)8-18-9-3-5-10(19-2)6-4-9/h3-7H,8H2,1-2H3
  • Key:MIWWSGDADVMLTG-UHFFFAOYSA-N

Common side effects include nausea, vomiting, headache, and trouble sleeping.[5] Other side effects may include QT prolongation, psychosis, and low white blood cells.[6] It is unclear if use during pregnancy or breast feeding is safe.[6] Fexinidazole is in the antiparasitic and the nitroimidazole family of medications.[4] It is believed to work by turning on certain enzymes within the parasites that result in their death.[5]

Fexinidazole was first described in 1978.[7] It was given a positive opinion by the European Medicines Agency in 2018.[5] It is on the World Health Organization's List of Essential Medicines.[8][9] Development for sleeping sickness was funded by the Drugs for Neglected Diseases initiative in collaboration with Sanofi.[10] Fexinidazole was approved for medical use in the United States in July 2021.[1]

Medical use

Sleeping sickness

A trial in Africa found fexinidazole to be 91% effective at treating sleeping sickness.[5][11] Though less effective than nifurtimox with eflornithine in severe disease, fexinidazole has the benefit that it can be taken by mouth.[5]

Fexinidazole is the first drug candidate for the treatment of advanced-stage sleeping sickness in thirty years.[12]

Other

It has activity against Trypanosoma cruzi, Tritrichomonas foetus, Trichomonas vaginalis, Entamoeba histolytica,[13] and Trypanosoma brucei.[14] It has not been found to be useful for visceral leishmaniasis.[4]

Mechanism of action

The biologically relevant active metabolites in vivo are the sulfoxide and sulfone.[15][16]

History

Fexinidazole was discovered by the German pharmaceutical company Hoechst AG, but its development as a pharmaceutical was halted in the 1980s.[17]

Society and culture

Fexinidazole Winthrop, a Sanofi-Aventis product developed with the Drugs for Neglected Diseases Initiative (DNDi), received a positive endorsement from the European Medicines Agency in 2018, for use in non-European markets.[18][19] It was approved for the treatment of Trypanosoma brucei gambiense human African trypanosomiasis (HAT) in the Democratic Republic of the Congo (DRC) in December 2018.[20] Fexinidazole was included in the 'role of honour' in Préscrire magazine's 2020 prize list.

Veterinary use

Fexinidazole is promising in African animal trypanosomiasis. Torreele et al. 2010 found the drug to be effective against T. b. gambiense infection of mice, rats, rabbits and beagles. They also found no toxicity in any of them, including a lack of mutagenicity despite in vitro mutagenicity.[21]

References
  1. "Fexinidazole: FDA-Approved Drugs". U.S. Food and Drug Administration. Retrieved 16 July 2021.
  2. "Fexinidazole tablet". DailyMed. Retrieved 20 August 2021.
  3. DIMITROVA, Elena Kostadinova (22 January 2019). "Fexinidazole Winthrop H-W-2320". European Medicines Agency. Retrieved 12 November 2019.
  4. Deeks, ED (February 2019). "Fexinidazole: First Global Approval". Drugs. 79 (2): 215–220. doi:10.1007/s40265-019-1051-6. PMID 30635838. S2CID 57772417.
  5. "Fexinidazole Winthrop (fexinidazole)" (PDF). EMA. Archived from the original (PDF) on 2 January 2021. Retrieved 12 November 2019.
  6. "Fexinidazole Winthrop" (PDF). EMA. Archived from the original (PDF) on 12 November 2019. Retrieved 12 November 2019.
  7. Gil, Carmen; Rivas, Luis (2017). Drug Discovery for Leishmaniasis. Royal Society of Chemistry. p. 30. ISBN 9781788012584.
  8. 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.
  9. World Health Organization (2021). World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. hdl:10665/345533. WHO/MHP/HPS/EML/2021.02.
  10. "Fexinidazole – DNDi". www.dndi.org. 31 December 2004. Retrieved 12 November 2019.
  11. Mesu VK, Kalonji WM, Bardonneau C, et al. (4 November 2017). "Oral fexinidazole for late-stage African Trypanosoma brucei gambiense trypanosomiasis: a pivotal multicentre, randomised, non-inferiority trial". Lancet. 391 (10116): 144–154. doi:10.1016/s0140-6736(17)32758-7. ISSN 0140-6736. PMID 29113731. S2CID 46781585.
  12. Torreele, E; Bourdin Trunz, B; Tweats, D; Kaiser, M; Brun, R; Mazué, G; Bray, MA; Pécoul, B (2010). Boelaert, Marleen (ed.). "Fexinidazole--a new oral nitroimidazole drug candidate entering clinical development for the treatment of sleeping sickness". PLOS Neglected Tropical Diseases. 4 (12): e923. doi:10.1371/journal.pntd.0000923. PMC 3006138. PMID 21200426.
  13. Raether, W; Seidenath, H (1983). "The activity of fexinidazole (HOE 239) against experimental infections with Trypanosoma cruzi, trichomonads and Entamoeba histolytica". Annals of Tropical Medicine and Parasitology. 77 (1): 13–26. doi:10.1080/00034983.1983.11811668. PMID 6411009.
  14. Jennings, FW; Urquhart, GM (1983). "The use of the 2 substituted 5-nitroimidazole, Fexinidazole (Hoe 239) in the treatment of chronic T. brucei infections in mice". Zeitschrift für Parasitenkunde. 69 (5): 577–581. doi:10.1007/bf00926669. PMID 6636983. S2CID 24432113.
  15. Wyllie S, Patterson S, Stojanovski L, et al. (2012). "The anti-trypanosome drug fexinidazole shows potential for treating visceral leishmaniasis". Science Translational Medicine. 4 (119): 119re1. doi:10.1126/scitranslmed.3003326. PMC 3457684. PMID 22301556.
  16. Sokolova AY, Wyllie S, Patterson S, et al. (2010). "Cross-resistance to nitro drugs and implications for treatment of human African trypanosomiasis". Antimicrobial Agents and Chemotherapy. 54 (7): 2893–900. doi:10.1128/AAC.00332-10. PMC 2897277. PMID 20439607.
  17. McNeil, Jr., Donald (8 January 2008). "Jump-Start on Slow Trek to Treatment for a Disease". The New York Times.
  18. "CHMP Summary of Opinion - Fexinidazole Winthrop" (PDF). Retrieved 19 November 2018.
  19. McNeil, Jr., Donald (16 November 2018). "Rapid Cure Approved for Sleeping Sickness, a Horrific Illness". The New York Times. Retrieved 20 November 2018.
  20. "Fexinidazole, the first all-oral treatment for sleeping sickness, approved in Democratic Republic of Congo". Drugs for Neglected Diseases Initiative (DNDi). 29 January 2019. Retrieved 4 June 2019.
  21. Kennedy, Peter G. E. (2013). "Clinical". The. Elsevier. 12 (2): 186–194. doi:10.1016/s1474-4422(12)70296-x. ISSN 1474-4422. PMID 23260189. S2CID 8688394.
  • "Fexinidazole". Drug Information Portal. U.S. National Library of Medicine.
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