Pharmacokinetics, Trypanosoma brucei gambiense Efficacy, and Time of Drug Action of DB829, a Preclinical Candidate for Treatment of Second-Stage Human African Trypanosomiasis

Abstract

ABSTRACTHuman African trypanosomiasis (HAT, also called sleeping sickness), a neglected tropical disease endemic to sub-Saharan Africa, is caused by the parasitesTrypanosoma brucei gambienseandT. brucei rhodesiense. Current drugs against this disease have significant limitations, including toxicity, increasing resistance, and/or a complicated parenteral treatment regimen. DB829 is a novel aza-diamidine that demonstrated excellent efficacy in mice infected withT. b. rhodesienseorT. b. bruceiparasites. The current study examined the pharmacokinetics,in vitroandin vivoactivity againstT. b. gambiense, and time of drug action of DB829 in comparison to pentamidine. DB829 showed outstandingin vivoefficacy in mice infected with parasites ofT. b. gambiensestrains, despite having higherin vitro50% inhibitory concentrations (IC50s) than againstT. b. rhodesiensestrain STIB900. A single dose of DB829 administered intraperitoneally (5 mg/kg of body weight) cured all mice infected with differentT. b. gambiensestrains. No cross-resistance was observed between DB829 and pentamidine inT. b. gambiensestrains isolated from melarsoprol-refractory patients. Compared to pentamidine, DB829 showed a greater systemic exposure when administered intraperitoneally, partially contributing to its improved efficacy. Isothermal microcalorimetry andin vivotime-to-kill studies revealed that DB829 is a slower-acting trypanocidal compound than pentamidine. A single dose of DB829 (20 mg/kg) administered intraperitoneally clears parasites from mouse blood within 2 to 5 days. In summary, DB829 is a promising preclinical candidate for the treatment of first- and second-stage HAT caused by bothTrypanosoma bruceisubspecies.