Antitrypanosomal Activity of Fexinidazole Metabolites, Potential New Drug Candidates for Chagas Disease

Abstract

cThis study was designed to verify the in vivo efficacy of sulfoxide and sulfone fexinidazole metabolites following oral administration in a murine model of Chagas disease. Female Swiss mice infected with the Y strain of Trypanosoma cruzi were treated orally once per day with each metabolite at doses of 10 to 100 mg/kg of body weight for a period of 20 days. Parasitemia was monitored throughout, and cures were detected by parasitological and PCR assays. The results were compared with those achieved with benznidazole treatment at the same doses. Fexinidazole metabolites were effective in reducing the numbers of circulating parasites and protecting mice against death, compared with untreated mice, but without providing cures at daily doses of 10 and 25 mg/kg. Both metabolites were effective in curing mice at 50 mg/kg/day (30% to 40%) and 100 mg/kg/day (100%). In the benznidazole-treated group, parasitological cure was detected only in animals treated with the higher dose of 100 mg/kg/day (80%). Single-dose pharmacokinetic parameters for each metabolite were obtained from a parallel group of uninfected mice and were used to estimate the profiles following repeated doses. Pharmacokinetic data suggested that biological efficacy most likely resides with the sulfone metabolite (or subsequent reactive metabolites formed following reduction of the nitro group) following administration of either the sulfoxide or the sulfone and that prolonged plasma exposure over the 24-h dosing window is required to achieve high cure rates. Fexinidazole metabolites were effective in treating T. cruzi in a mouse model of acute infection, with cure rates superior to those achieved with either fexinidazole itself or benznidazole.

Antitrypanosomal Activity of Sterol 14α-Demethylase (CYP51) Inhibitors VNI and VFV in the Swiss Mouse Models of Chagas Disease Induced by the Trypanosoma cruzi Y Strain

“…For example, a clinical trial of another nitroderivative, fexinidazole, that was very active in preclinical assays (15) has been stopped and the compound was discarded as a drug candidate because of its severe toxic profile in chagasic patients (19). The results of clinical trials of two antifungal agents, posaconazole and ravuconazole, have not met expectations.…”

“…These compounds, however, have several limitations, including serious adverse side effects, which lead to treatment discontinuation in 15 to 30% of patients (10,13), lack of efficacy in the later chronic phase of the disease, and the occurrence of several naturally resistant strains of T. cruzi (14)(15)(16). In both nitroderivatives (as well as the nitroimidazole fexinidazole, which was under recent clinical trial for CD), the nitro group is expected to undergo reductive metabolism catalyzed by parasite nitroreductases, leading to the formation of biologically active species exerting their trypanocidal activity (15). Because of their toxicity, neither Bz nor nifurtimox is approved by the FDA and therefore they are not sold or prescribed in the United States.…”

Concomitant Benznidazole and Suramin Chemotherapy in Mice Infected with a Virulent Strain of Trypanosoma cruzi

“…Since the 1960s, the compound N-benzyl-2-nitroimidazole acetamide (benznidazole [Bz]) has been the first-line drug against T. cruzi infection. Although chemotherapy with Bz is not always successful, no drugs with therapeutic efficiency superior to that of Bz are available (5)(6)(7). Clinical studies have also reported marked side effects of Bz associated with low specificity and systemic toxicity (1,5).…”

“…Clinical studies have also reported marked side effects of Bz associated with low specificity and systemic toxicity (1,5). These limitations have highlighted the need for more effective and suitable strategies for Chagas disease control (1,7).…”

Dose-dependent effect and pharmacokinetics of fexinidazole and its metabolites in a mouse model of human African trypanosomiasis

“…Fexinidazole has shown promising results in other kinetoplastid diseases, with its efficacy also being assessed against Chagas disease and leishmaniasis [23].…”