Jump to content

Fexinidazole

From Wikipedia, the free encyclopedia

This is an old revision of this page, as edited by Headbomb (talk | contribs) at 22:46, 17 October 2023 (ce). The present address (URL) is a permanent link to this revision, which may differ significantly from the current revision.

Fexinidazole
Clinical data
Other names
  • Fexinidazole Winthrop
  • HOE 239
License data
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Identifiers
  • 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 Edit this at Wikidata
Chemical and physical data
FormulaC12H13N3O3S
Molar mass279.31 g·mol−1
3D model (JSmol)
  • [O-] [N+](=O)c1cnc(n1C)COc2ccc(SC)cc2
  • 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

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] Also a potential new treatment for Chagas disease, a neglected tropical disease that affects millions of people worldwide.[4] It is taken by mouth.[5]

Common side effects include nausea, vomiting, headache, and trouble sleeping.[6] Other side effects may include QT prolongation, psychosis, and low white blood cells.[7] It is unclear if use during pregnancy or breast feeding is safe.[7] Fexinidazole is in the antiparasitic and the nitroimidazole family of medications.[5] It is believed to work by turning on certain enzymes within the parasites that result in their death.[6]

Fexinidazole was first described in 1978.[8] It was given a positive opinion by the European Medicines Agency in 2018.[6] It is on the World Health Organization's List of Essential Medicines.[9][10] Development for sleeping sickness was funded by the Drugs for Neglected Diseases initiative in collaboration with Sanofi.[11] 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.[6][12] Though less effective than nifurtimox with eflornithine in severe disease, fexinidazole has the benefit that it can be taken by mouth.[6]

Fexinidazole is the first drug candidate for the treatment of advanced-stage sleeping sickness in thirty years.[13]

Efficacy and safety

In cell culture, fexinidazole has an IC50 of around 1–4μM against Trypanosoma brucei.[14] In the mouse model, fexinidazole cures both the first, haemolymphatic, and the second, meningoencephalitic stage of the infection, the latter at 100 mg/kg twice daily for 5 days. In patients, the clinical trials managed by DNDi and supported by Swiss TPH mainly conducted in the Democratic Republic of the Congo demonstrated that oral fexinidazole is safe and effective for use against first- and early second-stage sleeping sickness. Based on the positive opinion issued by the European Medicines Agency in 2018, the WHO has released new interim guidelines for the treatment of HAT including fexinidazole as the new therapy for first-stage and non-severe second-stage sleeping sickness caused by Trypanosoma brucei gambiense (gHAT) [15] Recently, a study of the safety and efficacy of oral fexinidazole in children with gambiense human African trypanosomiasis was accomplished and concluded that orally administered fexinidazole showed high efficacy across all stages of gambiense human African trypanosomiasis infection in children aged 6 years and older and weighing more than 20 kg. The benefit-to-risk ratio of fexinidazole for treating children with gambiense human African trypanosomiasis, regardless of disease stage, is positive. Current interventions for diagnosing, staging, and treating gambiense human African trypanosomiasis require resources, trained personnel, equipment, and hospital infrastructure. These potentially costly procedures are therefore difficult to implement in remote areas or in those that might be mired in conflict, which could prevent the goal of eliminating gambiense human African trypanosomiasis by 2030.25,26 Simplified oral treatments such as fexinidazole or single-dose oral treatments such as acoziborole (currently in clinical trials)27 that can cure both disease stages of gambiense human African trypanosomiasis and circumvent the need for systematic disease staging with lumbar puncture (a procedure associated with complications and anxiety, particularly in children28) would benefit both patients and health-care professionals [16] Furthermore, Damasio et al. evaluated the in vivo oral efficacy of self-emulsifying drug delivery systems (SEDDS) containing fexinidazole (FEX) in the experimental treatment of visceral leishmaniasis (VL). The developed FEX-SEDDS formulation presented as a clear, yellowish liquid without precipitate. In the simulated gastric and intestinal media, the FEX-SEDDS had a size of 97 ± 1 and 106 ± 9 nm, respectively. The FEX retention in droplets after SEDDS dilution in simulated gastrointestinal media was almost 100%. Antileishmanial efficacy studies showed that FEX-SEDDS was the only treatment able to significantly (p < 0.05) reduce the parasite burden in the liver and spleen of animals experimentally infected with Leishmania infantum [17]

Mechanism of action

The biologically relevant active metabolites in vivo are the sulfoxide and sulfone.[18][19]

Synthesis

Synthetic pathway of fexinidzaole, adapted from Scheme 3 of McInturff et al. 2023.[20]

History

Fexinidazole was discovered by the German pharmaceutical company Hoechst AG, but its development as a pharmaceutical was halted in the 1980s.[21]

The US Food and Drug Administration granted the application for fexinidazole orphan drug designation.[22]

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.[23][24] 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.[25] Fexinidazole was included in the 'role of honour' in Préscrire magazine's 2020 prize list.Fexinidazole Winthrop° (fexinidazole) : au Tableau d'Honneur 2020

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.[26]

References

  1. ^ a b "Fexinidazole: FDA-Approved Drugs". U.S. Food and Drug Administration. Retrieved 16 July 2021.
  2. ^ "Fexinidazole tablet". DailyMed. Retrieved 20 August 2021.
  3. ^ a b DIMITROVA, Elena Kostadinova (22 January 2019). "Fexinidazole Winthrop H-W-2320". European Medicines Agency. Retrieved 12 November 2019.
  4. ^ Torrico, Faustino; Gascón, Joaquim; Ortiz, Lourdes; Pinto, Jimy; Rojas, Gimena; Palacios, Alejandro; Barreira, Fabiana; Blum, Bethania; Schijman, Alejandro Gabriel; Vaillant, Michel; Strub-Wourgaft, Nathalie; Pinazo, Maria-Jesus; Bilbe, Graeme; Ribeiro, Isabela (8 February 2023). "A Phase 2, Randomized, Multicenter, Placebo-Controlled, Proof-of-Concept Trial of Oral Fexinidazole in Adults With Chronic Indeterminate Chagas Disease". Clinical Infectious Diseases. 76 (3): e1186–e1194. doi:10.1093/cid/ciac579. ISSN 1537-6591. PMC 9907522. PMID 35925555.
  5. ^ a b Deeks, ED (February 2019). "Fexinidazole: First Global Approval". Drugs. 79 (2): 215–220. doi:10.1007/s40265-019-1051-6. PMID 30635838. S2CID 57772417.
  6. ^ a b c d e "Fexinidazole Winthrop (fexinidazole)" (PDF). EMA. Archived from the original (PDF) on 2 January 2021. Retrieved 12 November 2019.
  7. ^ a b "Fexinidazole Winthrop" (PDF). EMA. Archived from the original (PDF) on 12 November 2019. Retrieved 12 November 2019.
  8. ^ Gil, Carmen; Rivas, Luis (2017). Drug Discovery for Leishmaniasis. Royal Society of Chemistry. p. 30. ISBN 9781788012584.
  9. ^ 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.
  10. ^ 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.
  11. ^ "Fexinidazole – DNDi". www.dndi.org. 31 December 2004. Retrieved 12 November 2019.
  12. ^ 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.
  13. ^ 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.
  14. ^ Kaiser, Marcel; Bray, Michael A.; Cal, Monica; Bourdin Trunz, Bernadette; Torreele, Els; Brun, Reto (2011). "Antitrypanosomal Activity of Fexinidazole, a New Oral Nitroimidazole Drug Candidate for Treatment of Sleeping Sickness". Antimicrobial Agents and Chemotherapy. 55 (12). American Society for Microbiology: 5602–5608. doi:10.1128/aac.00246-11. ISSN 0066-4804. PMC 3232772. PMID 21911566.
  15. ^ Bernhard, Sonja; Kaiser, Marcel; Burri, Christian; Mäser, Pascal (2022). "Fexinidazole for Human African Trypanosomiasis, the Fruit of a Successful Public-Private Partnership". Diseases. 10 (90): 90. doi:10.3390/diseases10040090. PMC 9589988. PMID 36278589.
  16. ^ Kande Betu Kumesu, Victor; Mutombo Kalonji, Wilfried; Bardonneau, Clélia; Valverde Mordt, Olaf; Ngolo Tete, Digas; Blesson, Séverine; Simon, François; Delhomme, Sophie; Bernhard, Sonja; Nganzobo Ngima, Pathou; Mahenzi Mbembo, Hélène; Fina Lubaki, Jean-Pierre; Lumeya Vuvu, Steven; Kuziena Mindele, Willy; Kuziena Mindele, Willy; Ilunga Wa Kyhi, Médard; Mandula Mokenge, Guylain; Kaninda Badibabi, Lewis; Kasongo Bonama, Augustin; Kavunga Lukula, Papy; Lumbala, Crispin; Scherre, Bruno; Strub-Wourgaft, Nathali; Tarral, Antoine (2022). "Safety and efficacy of oral fexinidazole in children with gambiense human African trypanosomiasis: a multicentre, single-arm, open-label, phase 2–3 trial". The Lancet Global Health. 10 (11): e1665–e1674. doi:10.1016/S2214-109X(22)00338-2. PMC 9554014. PMID 36179736.
  17. ^ Damasio, Danielle S´oter do Nascimento; Antunes, Patrícia Andrade; Lages, Eduardo Burgarelli; Morais-Teixeira, Eliane de; Vital, Katia Duarte; Cardoso, Valbert Nascimento; Fernandes, Simone Odılia Antunes; Aguiar, Marta Gontijo; Ferreira, Lucas Antonio Miranda (2023). "A new oral self-emulsifying drug delivery system improves the antileishmania efficacy of fexinidazole in vivo". International Journal of Pharmaceutics. 631. doi:10.1016/j.ijpharm.2022.122505. PMID 36549405. S2CID 254917177.
  18. ^ 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.
  19. ^ 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.
  20. ^ McInturff, Emma L.; France, Scott P.; Leverett, Carolyn A.; Flick, Andrew C.; Lindsey, Erick A.; Berritt, Simon; Carney, Daniel W.; DeForest, Jacob C.; Ding, Hong X.; Fink, Sarah J.; Gibson, Tony S.; Gray, Kaitlyn; Hubbell, Aran K.; Johnson, Amber M.; Liu, Yiyang; Mahapatra, Subham; McAlpine, Indrawan J.; Watson, Rebecca B.; O’Donnell, Christopher J. (1 August 2023). "Synthetic Approaches to the New Drugs Approved During 2021". Journal of Medicinal Chemistry. 66 (15). American Chemical Society (ACS): 10150–10201. doi:10.1021/acs.jmedchem.3c00501. ISSN 0022-2623. PMID 37528515. S2CID 260377572.
  21. ^ McNeil, Jr., Donald (8 January 2008). "Jump-Start on Slow Trek to Treatment for a Disease". The New York Times.
  22. ^ Advancing Health Through Innovation: New Drug Therapy Approvals 2021 (PDF). U.S. Food and Drug Administration (FDA) (Report). 13 May 2022. Archived from the original on 6 December 2022. Retrieved 22 January 2023. Public Domain This article incorporates text from this source, which is in the public domain.
  23. ^ "CHMP Summary of Opinion - Fexinidazole Winthrop" (PDF). Retrieved 19 November 2018.
  24. ^ McNeil, Jr., Donald (16 November 2018). "Rapid Cure Approved for Sleeping Sickness, a Horrific Illness". The New York Times. Retrieved 20 November 2018.
  25. ^ "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.
  26. ^ Kennedy, Peter G. E. (2013). "Clinical". The. 12 (2). Elsevier: 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.
Retrieved from "https://en.wikipedia.org/w/index.php?title=Fexinidazole&oldid=1180645477"