Trypanosoma

Fexinidazole (HOE 239) has sulfoxide and sulfone as its two main metabolites. With IC50s ranging from 0.7-3.3 μM (0.2-0.9 μg/ml), they have demonstrated trypanocidal activity in vitro against every tested parasite strain[1].

Fexinidazole (HOE 239; four consecutive days; 20–50 mg/kg/day of IP or 25–100 mg/kg/day of PO) exhibits antitrypanosomal properties[1].

Adult female NMRI mice weighing between 20 and 25 g T. b. rhodesiense
20, 50 mg/kg (IP) or 25, 50, 100 mg/kg (PO)
IP or PO; daily; four consecutive days

Absorption, Distribution and Excretion
Fexinidazole is well absorbed, although the rate and extent of absorption are less than dose-proportional; after a 14-day administration schedule, the mean Cmax and AUClast 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 Tmax 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 Cmax 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 Cmax 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.
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.
Fexinidazole has an apparent volume of distribution of 3222 ± 1199 L.
Fexinidazole has a mean apparent day 4 clearance of 161 ± 37 L/h.

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Metabolism / Metabolites
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.

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Biological Half-Life
Fexinidazole, M1, and M2 have mean day 10 half-lives of 15 ± 6, 16 ± 6, and 23 ± 4 hours, respectively.

Hepatotoxicity
Fexinidazole therapy was not associated with elevations in aminotransferase or bilirubin levels or with clinically apparent liver injury during the ten day regimens used to treat African trypanosomiasis. However, evaluation of longer courses of therapy and use of higher doses in Chagas disease caused by Trypanosoma cruzi demonstrated several instances of ALT or AST elevations above 3 times the upper limit of normal (ULN), which persisted for as long as 3 months after stopping fexinidazole. The enzyme elevations were usually hepatocellular and arose after 2 weeks of therapy. The liver injury was asymptomatic and not associated with jaundice or with rash, fever or other signs of hypersensitivity. Nevertheless, the hepatic injury as well as delayed neutropenia led to discontinuation of the clinical trials of fexinidazole in high doses in Chagas disease. Since approval of fexinidazole for African trypanosomiasis, there have been no individual reports of liver injury associated with its use.
Likelihood score: E* (unlikely but suspected cause of clinically apparent liver injury when given in the recommended regimens for African trypanosomiasis).

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Protein Binding
Fexinidazole, M1, and M2 are approximately 98, 41, and 57 percent bound to plasma proteins, respectively.

[1]. Antitrypanosomal activity of fexinidazole, a new oral nitroimidazole drug candidate for treatment of sleeping sickness. Antimicrob Agents Chemother. 2011 Dec;55(12):5602-8.

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. 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 [disulfiram] itself; patients should avoid alcohol and [disulfiram] when taking fexinidazole.

C12H13N3O3S

279.314

279.067

C, 51.60; H, 4.69; N, 15.04; O, 17.18; S, 11.48

59729-37-2

68792

Solid powder

1.3±0.1 g/cm3

511.3±40.0 °C at 760 mmHg

263.0±27.3 °C

0.0±1.3 mmHg at 25°C

1.629

2.28

0

5

4

19

305

0

S(C([H])([H])[H])C1C([H])=C([H])C(=C([H])C=1[H])OC([H])([H])C1=NC([H])=C([N+](=O)[O-])N1C([H])([H])[H]

MIWWSGDADVMLTG-UHFFFAOYSA-N

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

1-methyl-2-[(4-methylsulfanylphenoxy)methyl]-5-nitroimidazole

Hoe239; Hoe 239; Fexinidazole; Hoe-239

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: 50~56 mg/mL (179.0~200.5 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (8.95 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: 2.5 mg/mL (8.95 mM) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)