Fexinidazole – A New Oral Nitroimidazole Drug Candidate Entering Clinical Development for the Treatment of Sleeping Sickness

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