Fexinidazole

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Fexinidazole
Fexinidazole.svg
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 InfoCard 100.207.619 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C12H13N3O3S
Molar mass 279.31 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]

Contents

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 1–4 μM against Trypanosoma brucei . [14] In the mouse model, fexinidazole cures both the first, hemolymphatic, 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. [16] [17]

Simplified oral treatments such as fexinidazole or single-dose oral treatments such as acoziborole (currently in clinical trials) 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 [18] Furthermore, Damasio et al. evaluated the in vivo oral efficacy of self-emulsifying drug delivery systems (SEDDS) containing fexinidazole 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 . [19]

Mechanism of action

The biologically relevant active metabolites in vivo are the sulfoxide and sulfone. [20] [21]

History

Fexinidazole was discovered by the German pharmaceutical company Hoechst AG, but its development as a pharmaceutical was halted in the 1980s. [22]

The US Food and Drug Administration granted the application for fexinidazole orphan drug designation. [23]

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. [24] [25] 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. [26] Fexinidazole was included in the 'role of honour' in Préscrire magazine's 2020 prize list. [27]

Veterinary use

Fexinidazole is promising in African animal trypanosomiasis. Torreele et al.[ citation needed ] 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. [17]

Synthesis

Fexinidazole can be synthesized in several steps from nitroimidazole. [28]

Synthetic pathway of fexinidzaole, adapted from Scheme 3 of McInturff et al. 2023. Fexinidazole synthesis.svg
Synthetic pathway of fexinidzaole, adapted from Scheme 3 of McInturff et al. 2023.

Related Research Articles

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African trypanosomiasis is an insect-borne parasitic infection of humans and other animals.

<span class="mw-page-title-main">Trypanosomatida</span> Group of single-celled parasitic organisms

Trypanosomatida is a group of kinetoplastid unicellular organisms distinguished by having only a single flagellum. The name is derived from the Greek trypano (borer) and soma (body) because of the corkscrew-like motion of some trypanosomatid species. All members are exclusively parasitic, found primarily in insects. A few genera have life-cycles involving a secondary host, which may be a vertebrate, invertebrate or plant. These include several species that cause major diseases in humans. Some trypanosomatida are intracellular parasites, with the important exception of Trypanosoma brucei.

<span class="mw-page-title-main">Tsetse fly</span> Genus of disease-spreading insects

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<span class="mw-page-title-main">Trypanosomiasis</span> Medical condition

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<i>Trypanosoma brucei</i> Species of protozoan parasite

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References

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  13. ↑ Torreele E, Bourdin Trunz B, Tweats D, Kaiser M, Brun R, Mazué G, et al. (December 2010). Boelaert M (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 M, Bray MA, Cal M, Bourdin Trunz B, Torreele E, Brun R (December 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. PMC   3232772 . PMID   21911566.
  15. ↑ Bernhard S, Kaiser M, Burri C, Mäser P (October 2022). "Fexinidazole for Human African Trypanosomiasis, the Fruit of a Successful Public-Private Partnership". Diseases. 10 (4): 90. doi: 10.3390/diseases10040090 . PMC   9589988 . PMID   36278589.
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  18. ↑ Kande Betu Kumesu V, Mutombo Kalonji W, Bardonneau C, Valverde Mordt O, Ngolo Tete D, Blesson S, et al. (November 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.
  19. ↑ Damasio DS, Antunes PA, Lages EB, Morais-Teixeira E, Vital KD, Cardoso VN, et al. (January 2023). "A new oral self-emulsifying drug delivery system improves the antileishmania efficacy of fexinidazole in vivo". International Journal of Pharmaceutics. 631: 122505. doi:10.1016/j.ijpharm.2022.122505. PMID   36549405. S2CID   254917177.
  20. ↑ Wyllie S, Patterson S, Stojanovski L, Simeons FR, Norval S, Kime R, et al. (February 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.
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  22. ↑ McNeil Jr D (8 January 2008). "Jump-Start on Slow Trek to Treatment for a Disease". The New York Times .
  23. ↑ 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.PD-icon.svg This article incorporates text from this source, which is in the public domain .
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  27. ↑ "Fexinidazole Winthrop° (fexinidazole) : au Tableau d'Honneur 2020".
  28. ↑ McInturff EL, France SP, Leverett CA, Flick AC, Lindsey EA, Berritt S, et al. (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. PMID   37528515. S2CID   260377572.
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