Fexinidazole

Identification

Summary

Fexinidazole is an orally bioavailable 2-substituted 5-nitroimidazole used to treat early- and late-stage human African trypanosomiasis caused by Trypanosoma brucei gambiense.

Generic Name

Fexinidazole

DrugBank Accession Number

DB12265

Background

Human African trypanosomiasis (HAT, also colloquially referred to as sleeping sickness), caused by T. brucei gambiense and T. brucei rhodesiense, remains a moderate risk (>1/10,000 inhabitants per year in endemic areas) despite focussed control efforts. Transmitted by the bite of an infected tsetse fly, HAT is biphasic with a first (hemolymphatic) stage that progresses to a second (meningoencephalitic) stage in which patients experience progressively worsening neurological symptoms and eventually die if left untreated.¹ Historical treatment options for meningoencephalitic HAT include melarsoprol, eflornithine, and nifurtimox/eflornithine combination therapy (NECT), though melarsoprol is highly toxic and each treatment requires lengthy infusions that are difficult to administer in resource-limited settings.^1,3 Fexinidazole, which was originally developed in the 1970s/80s by Hoechst AG and subsequently rediscovered through the Drugs for Neglected Diseases Initiative (DNDi) in 2005, is the first all-oral treatment for first and second stage HAT caused by T. brucei gambiense.^2,3

Fexinidazole received a positive opinion from the European Medicines Agency (EMA) in November 2018 and was approved by the FDA on July 16, 2021.^2,8 It is currently marketed by Sanofi-Aventis.⁸

Type

Small Molecule

Groups

Approved, Investigational

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Fexinidazole (DB12265)

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Weight

Average: 279.31
Monoisotopic: 279.067762465

Chemical Formula

C₁₂H₁₃N₃O₃S

Synonyms

• Fexinidazole

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Pharmacology

Indication

Fexinidazole is a nitroimidazole indicated for the treatment of both first-stage (hemolymphatic) and second-stage (meningoencephalitic) Trypanosoma brucei gambiense human African trypanosomiasis (HAT) in patients 6 years of age and older weighing at least 20 kg.⁸

Due to the decreased efficacy observed in patients with severe second stage HAT (cerebrospinal fluid white blood cell count (CSF-WBC) >100 cells/μL), fexinidazole should only be used in these patients if there are no other available treatment options.⁸

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Treatment of	Human african trypanosomiasis (hat)		••••••••••••		•••• •••••• •••••	••••••

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Pharmacodynamics

Fexinidazole is a 2-substituted 5-nitroimidazole that is likely activated by parasitic nitroreductases to highly reactive species, leading to DNA and protein damage and eventual parasite death.^2,3,8 The dosing schedule is designed to ensure a high enough concentration of fexinidazole and its reactive metabolites for at least 48 hours, which from in vitro studies was shown to be the minimum exposure time that was effectively trypanocidal.^4,5 Although fexinidazole is effective in late-stage T. brucei gambiense HAT, it is less effective than NECT therapy in patients with severe (cerebrospinal fluid white blood cell count (CSF-WBC) >100 cells/μL at baseline) disease. It should only be used in these patients if there are no other available treatment options. Fexinidazole has been shown to prolong the QT interval in a dose-dependent manner and was also associated with a higher incidence of insomnia, headache, tremors, psychiatric disorders, and suicidal ideation in clinical trials; patients with pre-existing conditions or concomitant medications that could aggravate any of these effects should be treated with caution. In addition, fexinidazole has been associated with neutropenia and elevations in liver transaminases, which should be monitored. Nitroimidazoles like fexinidazole have been associated with a disulfiram-like reaction when used concomitantly with alcohol and psychotic reactions when taken with disulfiram itself; patients should avoid alcohol and disulfiram when taking fexinidazole.⁸

Mechanism of action

Human African trypanosomiasis (HAT) is caused by two subspecies of Trypanosoma brucei, T. brucei gambiense and T. brucei rhodesiense, with T. brucei gambiense HAT accounting for ~97% of the total disease burden. Transmitted by the bite of an infected tsetse fly, HAT begins as a local infection at the bite site before disseminating throughout the blood and reticuloendothelial system (first or hemolymphatic stage) and eventually crossing the blood-brain barrier (second or meningoencephalitic stage). First stage T. brucei gambiense HAT is characterized by fever, headache, swollen lymph nodes, pruritus, and other non-specific symptoms. Progression to the second stage results in progressive deterioration of neurological function, including sleep disturbances (HAT is also referred to as sleeping sickness), tremors, ataxia, abnormal behaviour, confusion, and coma; myocarditis and endocrine hypothalamic-hypophyseal dysfunction may also be present. If left untreated, HAT is fatal.¹

Fexinidazole is the first all-oral treatment for T. brucei gambiense HAT.² Both fexinidazole and its two main metabolites, a sulfoxide (M1) and sulfone (M2) metabolite, possess in vitro activity against T. brucei gambiense, T. brucei rhodesiense, and T. brucei brucei in the 0.2-0.9 μg/mL range.^3,4 Further studies revealed in vivo efficacy in HAT animal models and acceptable toxicity profiles, both in animal and human subjects.^3,4,5 Crucially, fexinidazole was shown to be non-inferior to existing nifurtimox/eflornithine combination therapy (NECT) in late-stage T. brucei gambiense infection.⁶

The precise mechanism of action of fexinidazole remains unknown. However, it is suggested that bacterial-like nitroreductases encoded by trypanosomes activate fexinidazole and its M1/M2 metabolites through reduction to form reactive intermediates capable of damaging DNA and proteins.^2,3,8 Whole-body autoradiography of [14C]-labelled fexinidazole in rats revealed broad distribution into all tissues, including an observed brain-to-blood concentration ratio of 0.4-0.6.³ Therefore, fexinidazole is capable of direct toxicity against trypanosomes throughout the body and in the brain, which is consistent with its efficacy against both early and late-stage infections.^3,4,6

Absorption

Fexinidazole is well absorbed, although the rate and extent of absorption are less than dose-proportional; after a 14-day administration schedule, the mean C_max and AUC_last increased by 1.17 and 1.34, or by 1.5 and 1.61, when the dose was either doubled or tripled.⁵ Following absorption, fexinidazole is rapidly converted to its M1 metabolite, which undergoes a slower transformation to M2 over time. This is reflected in the T_max of fexinidazole, M1, and M2 as 4 (0-9), 4 (0-6), and 6 (0-24) hours, respectively.^5,8

In healthy adults given an 1800 mg loading dose followed by 1200 mg daily over 14 days, the mean C_max for fexinidazole was 1.6 ± 0.4 μg/mL on day 1, 0.8 ± 0.3 μg/mL on day 2, and 0.5 ± 0.2 μg/mL on day 3. The relevant values for M1 were 8.1 ± 2.2, 8.0 ± 2.3, and 5.9 ± 2.1, while for M2 they were 7.5 ± 3.3, 19.6 ± 5.4, and 12.5 ± 3.5 μg/mL. Similarly, the AUC for fexinidazole was 14.3 ± 2.6, 11.6 ± 2.2, and 7.0 ± 2.5, for M1 was 102.3 ± 28.5, 127.9 ± 49.2, and 84.2 ± 36.3, and for M2 was 110.1 ± 41.1, 391.5 ± 126.7, and 252.4 ± 73.6 μg*h/mL.^5,8 Concomitant food intake increases the C_max and AUC of fexinidazole, M1, and M2 by 2-5 fold without significantly changing the metabolite ratios.^5,8

There are no clear effects of age, renal, or hepatic impairment on absorption or plasma parameters of fexinidazole or its metabolites; further studies may be required to confirm/refute these observations.⁸

Volume of distribution

Fexinidazole has an apparent volume of distribution of 3222 ± 1199 L.⁸

Protein binding

Fexinidazole, M1, and M2 are approximately 98, 41, and 57 percent bound to plasma proteins, respectively.^5,8

Metabolism

Fexinidazole is metabolized by a variety of enzymes including the CYP450 enzymes CYP1A2, 2B6, 2C19, 2D6, 3A4, and 3A5 as well as flavin mono-oxygenase-3 (FMO-3). Fexinidazole is first transformed to the sulfoxide M1 and then the sulfone M2, which does not appear to undergo further metabolism.^3,5,8

Hover over products below to view reaction partners

• Fexinidazole
  • Fexinidazole sulfoxide metabolite (M1)
    • Fexinidazole sulfone metabolite (M2)

Route of elimination

Elimination is almost entirely extra-renal; roughly 0.75-3.15% of a fexinidazole dose was recovered in urine over 168 h, primarily as M1 and M2 metabolites.^5,8

Half-life

Fexinidazole, M1, and M2 have mean day 10 half-lives of 15 ± 6, 16 ± 6, and 23 ± 4 hours, respectively.^5,8

Clearance

Fexinidazole has a mean apparent day 4 clearance of 161 ± 37 L/h.⁸

Adverse Effects

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Toxicity

Healthy male adult volunteers were administered single or multiple daily doses of up to 3600 mg for 14 days and experienced elevated liver transaminases, vomiting, and panic attacks. Pediatric HAT patients given higher than recommended doses experienced vomiting, increased potassium, and decreased calcium levels. There is no specific antidote to fexinidazole; symptomatic and supportive measures are recommended in case of overdose.⁸

Rats and beagles given up to 800 mg/kg/day of fexinidazole showed mild appetite and body weight alterations but no clear hepatotoxicity. Fexinidazole did not induce any effects on embryo-fetal and postnatal development when administered to pregnant rats. Although fexinidazole is mutagenic in a standard Ames test, it is not anticipated to be genotoxic in humans.³

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abametapir	The serum concentration of Fexinidazole can be increased when it is combined with Abametapir.
Abatacept	The metabolism of Fexinidazole can be increased when combined with Abatacept.
Abemaciclib	The serum concentration of Abemaciclib can be increased when it is combined with Fexinidazole.
Abiraterone	The serum concentration of Fexinidazole can be increased when it is combined with Abiraterone.
Abrocitinib	The metabolism of Abrocitinib can be decreased when combined with Fexinidazole.

Food Interactions

• Take with food. Food assists in fexinidazole absorption.

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Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Fexinidazole	Tablet	600 mg/1	Oral	sanofi-aventis U.S. LLC	2021-07-16	Not applicable

Categories

ATC Codes

P01CA03 — Fexinidazole

• P01CA — Nitroimidazole derivatives
• P01C — AGENTS AGAINST LEISHMANIASIS AND TRYPANOSOMIASIS
• P01 — ANTIPROTOZOALS
• P — ANTIPARASITIC PRODUCTS, INSECTICIDES AND REPELLENTS

Drug Categories

• Agents Against Leishmaniasis and Trypanosomiasis
• Antiparasitic Products, Insecticides and Repellents
• Antiprotozoals
• Cytochrome P-450 CYP1A2 Inducers
• Cytochrome P-450 CYP1A2 Inducers (strength unknown)
• Cytochrome P-450 CYP1A2 Inhibitors
• Cytochrome P-450 CYP1A2 Inhibitors (strength unknown)
• Cytochrome P-450 CYP1A2 Substrates
• Cytochrome P-450 CYP2B6 Inducers
• Cytochrome P-450 CYP2B6 Inducers (strength unknown)
• Cytochrome P-450 CYP2B6 Inhibitors
• Cytochrome P-450 CYP2B6 Inhibitors (strength unknown)
• Cytochrome P-450 CYP2B6 Substrates
• Cytochrome P-450 CYP2C19 Inhibitors
• Cytochrome P-450 CYP2C19 inhibitors (strength unknown)
• Cytochrome P-450 CYP2C19 Substrates
• Cytochrome P-450 CYP2D6 Inhibitors
• Cytochrome P-450 CYP2D6 Inhibitors (strength unknown)
• Cytochrome P-450 CYP2D6 Substrates
• Cytochrome P-450 CYP3A Inhibitors
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Inhibitors
• Cytochrome P-450 CYP3A4 Inhibitors (strength unknown)
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 CYP3A5 Inhibitors
• Cytochrome P-450 CYP3A5 Inhibitors (strength unknown)
• Cytochrome P-450 CYP3A5 Substrates
• Cytochrome P-450 Enzyme Inducers
• Cytochrome P-450 Enzyme Inhibitors
• Cytochrome P-450 Substrates
• Imidazoles
• MATE 1 Inhibitors
• MATE 2 Inhibitors
• MATE 2-K Inhibitors
• MATE inhibitors
• Nitro Compounds
• Nitroimidazole Antimicrobial
• Nitroimidazole Derivatives
• OAT1/SLC22A6 inhibitors
• OAT3/SLC22A8 Inhibitors
• OATP1B1/SLCO1B1 Inhibitors
• OATP1B3 inhibitors
• OCT2 Inhibitors
• Organic Anion Transporter 1 Inhibitors
• Organic Anion Transporting Polypeptide 1B1 Inhibitors
• Organic Anion Transporting Polypeptide 1B3 Inhibitors

Chemical TaxonomyProvided by Classyfire

Description

This compound belongs to the class of organic compounds known as nitroimidazoles. These are compounds containing an imidazole ring which bears a nitro group.

Kingdom

Organic compounds

Super Class

Organoheterocyclic compounds

Class

Azoles

Sub Class

Imidazoles

Direct Parent

Nitroimidazoles

Alternative Parents

Thiophenol ethers / 1,2,5-trisubstituted imidazoles / Phenoxy compounds / Phenol ethers / Nitroaromatic compounds / Alkyl aryl ethers / Alkylarylthioethers / N-substituted imidazoles / Heteroaromatic compounds / Organic oxoazanium compounds / Sulfenyl compounds / Azacyclic compounds / Propargyl-type 1,3-dipolar organic compounds / Organonitrogen compounds / Hydrocarbon derivatives / Organopnictogen compounds / Organic oxides

show 7 more

Substituents

1,2,5-trisubstituted-imidazole / Alkyl aryl ether / Alkylarylthioether / Allyl-type 1,3-dipolar organic compound / Aromatic heteromonocyclic compound / Aryl thioether / Azacycle / Benzenoid / C-nitro compound / Ether / Heteroaromatic compound / Hydrocarbon derivative / Monocyclic benzene moiety / N-substituted imidazole / Nitroaromatic compound / Nitroimidazole / Organic 1,3-dipolar compound / Organic nitro compound / Organic nitrogen compound / Organic oxide / Organic oxoazanium / Organic oxygen compound / Organonitrogen compound / Organooxygen compound / Organopnictogen compound / Organosulfur compound / Phenol ether / Phenoxy compound / Propargyl-type 1,3-dipolar organic compound / Sulfenyl compound / Thioether / Thiophenol ether / Trisubstituted imidazole

show 23 more

Molecular Framework

Aromatic heteromonocyclic compounds

External Descriptors

Not Available

Affected organisms

• Trypanosoma brucei gambiense

Chemical Identifiers

UNII

306ERL82IR

CAS number

59729-37-2

InChI Key

MIWWSGDADVMLTG-UHFFFAOYSA-N

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

IUPAC Name

1-methyl-2-{[4-(methylsulfanyl)phenoxy]methyl}-5-nitro-1H-imidazole

SMILES

CSC1=CC=C(OCC2=NC=C(N2C)[N+]([O-])=O)C=C1

References

Synthesis Reference

Winkelmann E, Raether W, Gebert U, Sinharay A (1977) Chemotherapeutically active nitro compounds. 4. 5-nitroimidazoles (Part I-IV). Arzneimittelforschung 27-28.

General References

1. Bottieau E, Clerinx J: Human African Trypanosomiasis: Progress and Stagnation. Infect Dis Clin North Am. 2019 Mar;33(1):61-77. doi: 10.1016/j.idc.2018.10.003. [Article]
2. Deeks ED: Fexinidazole: First Global Approval. Drugs. 2019 Feb;79(2):215-220. doi: 10.1007/s40265-019-1051-6. [Article]
3. Torreele E, Bourdin Trunz B, Tweats D, Kaiser M, Brun R, Mazue G, Bray MA, Pecoul B: Fexinidazole--a new oral nitroimidazole drug candidate entering clinical development for the treatment of sleeping sickness. PLoS Negl Trop Dis. 2010 Dec 21;4(12):e923. doi: 10.1371/journal.pntd.0000923. [Article]
4. Kaiser M, Bray MA, Cal M, Bourdin Trunz B, Torreele E, Brun R: Antitrypanosomal activity of fexinidazole, a new oral nitroimidazole drug candidate for treatment of sleeping sickness. Antimicrob Agents Chemother. 2011 Dec;55(12):5602-8. doi: 10.1128/AAC.00246-11. Epub 2011 Sep 12. [Article]
5. Tarral A, Blesson S, Mordt OV, Torreele E, Sassella D, Bray MA, Hovsepian L, Evene E, Gualano V, Felices M, Strub-Wourgaft N: Determination of an optimal dosing regimen for fexinidazole, a novel oral drug for the treatment of human African trypanosomiasis: first-in-human studies. Clin Pharmacokinet. 2014 Jun;53(6):565-80. doi: 10.1007/s40262-014-0136-3. [Article]
6. Mesu VKBK, Kalonji WM, Bardonneau C, Mordt OV, Blesson S, Simon F, Delhomme S, Bernhard S, Kuziena W, Lubaki JF, Vuvu SL, Ngima PN, Mbembo HM, Ilunga M, Bonama AK, Heradi JA, Solomo JLL, Mandula G, Badibabi LK, Dama FR, Lukula PK, Tete DN, Lumbala C, Scherrer B, Strub-Wourgaft N, Tarral A: Oral fexinidazole for late-stage African Trypanosoma brucei gambiense trypanosomiasis: a pivotal multicentre, randomised, non-inferiority trial. Lancet. 2018 Jan 13;391(10116):144-154. doi: 10.1016/S0140-6736(17)32758-7. Epub 2017 Nov 4. [Article]
7. Jennings FW, Urquhart GM: The use of the 2 substituted 5-nitroimidazole, Fexinidazole (Hoe 239) in the treatment of chronic T. brucei infections in mice. Z Parasitenkd. 1983;69(5):577-81. doi: 10.1007/BF00926669. [Article]
8. FDA Approved Drug Products: Fexinidazole tablets for oral use [Link]
9. Sigma-Aldrich: Fexinidazole SDS [Link]

External Links

PubChem Compound

68792

PubChem Substance

347828537

ChemSpider

62032

RxNav

2564146

ChEMBL

CHEMBL1631694

ZINC

ZINC000000001448

Wikipedia

Fexinidazole

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
3	Completed	Treatment	Trypanosoma Brucei Gambiense; Infection / Trypanosomiasis; Gambian	1
2	Completed	Treatment	Chagas' Disease (Chronic) Nos	1
2	Terminated	Treatment	Visceral Leishmaniasis	1
2	Unknown Status	Treatment	Chagas Disease / Trypanosomiasis, South American	1
2, 3	Completed	Treatment	Human African Trypanosomiasis (HAT)	2

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Tablet	Oral	600 mg/1

Prices

Not Available

Patents

Not Available

Properties

State

Solid

Experimental Properties

Property	Value	Source
boiling point (°C)	501	MSDS
water solubility	Practically insoluble	FDA Label

Predicted Properties

Property	Value	Source
Water Solubility	0.0927 mg/mL	ALOGPS
logP	2.28	ALOGPS
logP	2.38	Chemaxon
logS	-3.5	ALOGPS
pKa (Strongest Basic)	1.03	Chemaxon
Physiological Charge	0	Chemaxon
Hydrogen Acceptor Count	4	Chemaxon
Hydrogen Donor Count	0	Chemaxon
Polar Surface Area	70.19 Å2	Chemaxon
Rotatable Bond Count	5	Chemaxon
Refractivity	72.64 m3·mol-1	Chemaxon
Polarizability	28.53 Å3	Chemaxon
Number of Rings	2	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	Yes	Chemaxon
Ghose Filter	Yes	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	No	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted GC-MS Spectrum - GC-MS	Predicted GC-MS	splash10-000i-5960000000-1a2afbed3cec3c85a061
Predicted 1H NMR Spectrum	1D NMR	Not Applicable
Predicted 13C NMR Spectrum	1D NMR	Not Applicable

Chromatographic Properties

Collision Cross Sections (CCS)

Adduct	CCS Value (Å2)	Source type	Source
[M-H]-	174.6266032	predicted	DarkChem Lite v0.1.0
[M-H]-	158.17888	predicted	DeepCCS 1.0 (2019)
[M+H]+	175.0183032	predicted	DarkChem Lite v0.1.0
[M+H]+	160.81828	predicted	DeepCCS 1.0 (2019)
[M+Na]+	174.8012032	predicted	DarkChem Lite v0.1.0
[M+Na]+	168.31555	predicted	DeepCCS 1.0 (2019)

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Drug created at October 20, 2016 21:45 / Updated at April 06, 2022 23:53