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General Description:

Fexinidazole, identified by CAS number 59729-37-2, is a notable compound with significant therapeutic applications. 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. Historical treatment options for meningoencephalitic HAT include , , and / combination therapy (NECT), though is highly toxic and each treatment requires lengthy infusions that are difficult to administer in resource-limited settings. 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_. Fexinidazole received a positive opinion from the European Medicines Agency (EMA) in November 2018 and was approved by the FDA on July 16, 2021. It is currently marketed by Sanofi-Aventis.

Indications:

This drug is primarily indicated for: 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. 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. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Fexinidazole undergoes metabolic processing primarily in: 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. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Fexinidazole are crucial for its therapeutic efficacy: 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. 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. 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. Concomitant food intake increases the C_max and AUC of fexinidazole, M1, and M2 by 2-5 fold without significantly changing the metabolite ratios. 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. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Fexinidazole is an important consideration for its dosing schedule: Fexinidazole, M1, and M2 have mean day 10 half-lives of 15 ± 6, 16 ± 6, and 23 ± 4 hours, respectively. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Fexinidazole exhibits a strong affinity for binding with plasma proteins: Fexinidazole, M1, and M2 are approximately 98, 41, and 57 percent bound to plasma proteins, respectively. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Fexinidazole from the body primarily occurs through: 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. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Fexinidazole is distributed throughout the body with a volume of distribution of: Fexinidazole has an apparent volume of distribution of 3222 ± 1199 L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Fexinidazole is a critical factor in determining its safe and effective dosage: Fexinidazole has a mean apparent day 4 clearance of 161 ± 37 L/h. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Fexinidazole exerts its therapeutic effects through: 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. 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. 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 itself; patients should avoid alcohol and when taking fexinidazole. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Fexinidazole functions by: 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. Fexinidazole is the first all-oral treatment for _T. brucei gambiense_ HAT. 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. Further studies revealed _in vivo_ efficacy in HAT animal models and acceptable toxicity profiles, both in animal and human subjects. Crucially, fexinidazole was shown to be non-inferior to existing / combination therapy (NECT) in late-stage _T. brucei gambiense_ infection. 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. Whole-body autoradiography of -labelled fexinidazole in rats revealed broad distribution into all tissues, including an observed brain-to-blood concentration ratio of 0.4-0.6. 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. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Fexinidazole belongs to the class of organic compounds known as nitroimidazoles. These are compounds containing an imidazole ring which bears a nitro group, classified under the direct parent group Nitroimidazoles. This compound is a part of the Organic compounds, falling under the Organoheterocyclic compounds superclass, and categorized within the Azoles class, specifically within the Imidazoles subclass.

Categories:

Fexinidazole is categorized under the following therapeutic classes: 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. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Fexinidazole include:

• Water Solubility: Practically insoluble
• Boiling Point: 501