Safety, Pharmacokinetic, and Efficacy Studies of Oral DB868 in a First Stage Vervet Monkey Model of Human African Trypanosomiasis

摘要: There are no oral drugs for human African trypanosomiasis (HAT, sleeping sickness). A successful drug would have the potential to reduce or eliminate need patient hospitalization, thus reducing healthcare costs of HAT. The development medications is a key objective Consortium Parasitic Drug Development (CPDD). In this study, we investigated safety, pharmacokinetics, and efficacy new orally administered CPDD diamidine prodrug, 2,5-bis[5-(N-methoxyamidino)-2-pyridyl]furan (DB868; CPD-007-10), in vervet monkey model first stage DB868 was well tolerated at dose up 30 mg/kg/day 10 days, cumulative 300 mg/kg. Mean plasma levels biomarkers indicative liver injury (alanine aminotransferase, aspartate aminotransferase) were not significantly altered by administration. addition, kidney-mediated alterations creatinine urea concentrations detected. Pharmacokinetic analysis confirmed that available converted active compound DB829 both uninfected infected monkeys. Treatment monkeys with began 7 days post-infection. monkeys, attained median Cmax (dosing regimen) 12-fold (3 days), 15-fold (10 31-fold (20 5 days) greater than IC50 (14 nmol/L) against T. b. rhodesiense STIB900. cured all even lowest tested. conclusion, HAT 14-fold lower maximum should be considered lead preclinical candidate efforts develop safe, short course (5–7 regimen