Human
African trypanosomiasis (HAT), also known as sleeping sickness, is a fatal
parasitic disease caused by trypanosomes. Current treatment options for HAT are scarce, toxic, no longer effective, or very difficult to administer, in particular for the advanced, fatal stage of the disease (stage 2, chronic HAT). New safe, effective and easy-to-use treatments are urgently needed. Here it is shown that
fexinidazole, a 2-substituted
5-nitroimidazole rediscovered by the Drugs for
Neglected Diseases initiative (DNDi) after extensive compound mining efforts of more than 700 new and existing nitroheterocycles, could be a short-course, safe and effective oral treatment curing both acute and chronic HAT and that could be implemented at the primary health care level. To complete the preclinical development and meet the regulatory requirements before initiating human trials, the anti-parasitic properties and the pharmacokinetic, metabolic and toxicological profile of
fexinidazole have been assessed.
METHODS AND FINDINGS: Standard in vitro and in vivo anti-parasitic activity assays were conducted to assess
drug efficacy in experimental models for HAT. In parallel, a full range of preclinical pharmacology and safety studies, as required by international regulatory guidelines before initiating human studies, have been conducted.
Fexinidazole is moderately active in vitro against African trypanosomes (IC₅₀ against laboratory strains and recent clinical isolates ranged between 0.16 and 0.93 µg/mL) and
oral administration of
fexinidazole at doses of 100 mg/kg/day for 4 days or 200 mg/kg/day for 5 days cured mice with acute and
chronic infection respectively, the latter being a model for the advanced and fatal stage of the disease when parasites have disseminated into the brain. In laboratory animals,
fexinidazole is well absorbed after
oral administration and readily distributes throughout the body, including the brain. The absolute bioavailability of oral
fexinidazole was 41% in mice, 30% in rats, and 10% in dogs. Furthermore,
fexinidazole is rapidly metabolised in vivo to at least two biologically active metabolites (a
sulfoxide and a
sulfone derivative) that likely account for a significant portion of the
therapeutic effect. Key pharmacokinetic parameter after oral absorption in mice for
fexinidazole and its
sulfoxide and
sulfone metabolites are a C(max) of 500, 14171 and 13651 ng/mL respectively, and an AUC₀₋₂₄ of 424, 45031 and 96286 h.ng/mL respectively. Essentially similar PK profiles were observed in rats and dogs. Toxicology studies (including safety pharmacology and 4-weeks repeated-dose toxicokinetics in rat and dog) have shown that
fexinidazole is well tolerated. The No Observed Adverse Event Levels in the 4-weeks repeated dose toxicity studies in rats and dogs was 200 mg/kg/day in both species, with no issues of concern identified for doses up to 800 mg/kg/day. While
fexinidazole, like many nitroheterocycles, is mutagenic in the Ames test due to bacterial specific metabolism, it is not genotoxic to mammalian cells in vitro or in vivo as assessed in an in vitro micronucleus test on human lymphocytes, an in vivo mouse bone marrow micronucleus test, and an ex vivo unscheduled
DNA synthesis test in rats.
CONCLUSIONS: The results of the preclinical pharmacological and safety studies indicate that
fexinidazole is a safe and effective oral
drug candidate with no untoward effects that would preclude evaluation in man. The
drug has entered first-in-human phase I studies in September 2009.
Fexinidazole is the first new clinical
drug candidate with the potential for treating advanced-stage sleeping sickness in thirty years.