In vitro metabolism, disposition, preclinical pharmacokinetics and prediction of human pharmacokinetics of DNDI-VL-2098, a potential oral treatment for Visceral Leishmaniasis

Abstract

The in vitro metabolism and in vivo pharmacokinetic (PK) properties of DNDI-VL-2098, a potential oral agent for Visceral Leishmaniasis (VL) were studied and used to predict its human pharmacokinetics. DNDI-VL-2098 showed a low solubility (10μM) and was highly permeable (>200nm/s) in the Caco-2 model. It was stable in vitro in liver microsomes and hepatocytes and no metabolite was detectable in circulating plasma from dosed animals suggesting very slow, if any, metabolism of the compound. DNDI-VL-2098 was moderate to highly bound to plasma proteins across the species tested (94-98%). DNDI-VL-2098 showed satisfactory PK properties in mouse, hamster, rat and dog with a low blood clearance (<15% of hepatic blood flow except hamster), a volume of distribution of about 3 times total body water, acceptable half-life (1-6h across the species) and good oral bioavailability (37-100%). Allometric scaling of the preclinical PK data to human gave a blood half-life of approximately 20h suggesting that the compound could be a once-a-day drug. Based on the above assumptions, the minimum efficacious dose predicted for a 50kg human was 150mg and 300mg, using efficacy results in the mouse and hamster, respectively.

Activation of Bicyclic Nitro-drugs by a Novel Nitroreductase (NTR2) in Leishmania

“…This instability can be explained by the fact that delamanid is known to be primarily metabolised in plasma by albumin [18]. Likewise, DNDI-VL-2098 is reportedly unstable in plasma [9], presumably for the same reason.…”

“…The 2-substituted 5-nitroimidazole fexinidazole is now in clinical trials for use in the treatment of both HAT and VL [7] (www.dndi.org), and has shown potential for the treatment of Chagas disease [8]. In addition, until recently DND i had a nitroimidazole compound (DNDI-VL-2098) [9] and nitroimidazole back-up compounds at an advanced stage of pre-clinical development for use in the treatment of VL (www.dndi.org). Thus, nitroheterocyclic compounds look set to play an important role in the future treatment of these diseases.…”

Repositioning Antitubercular 6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazoles for Neglected Tropical Diseases: Structure–Activity Studies on a Preclinical Candidate for Visceral Leishmaniasis

“…56 For example, many nitroheterocyclic compounds provide positive results in the Ames test for mutagenicity; indeed, the development of an early 6-nitroimidazooxazole lead for TB (CGI-17341) was halted following such a discovery. 15 Extensive investigation by Otsuka Pharmaceutical Co. established that the introduction of heteroatoms and larger side chain functionality (e.g., 5) overcame this effect 18,57 and both 8 and 9 26 were Ames negative. Other safety factors (e.g., hERG, CYP inhibition, potential for drug-drug interactions) were also broadly acceptable for 9, 26 which additionally satisfied such criteria as high stability, low cost of synthesis and suitability for once-per-day oral administration noted in the proposed target product profile for a VL drug.…”

“…15 Extensive investigation by Otsuka Pharmaceutical Co. established that the introduction of heteroatoms and larger side chain functionality (e.g., 5) overcame this effect 18,57 and both 8 and 9 26 were Ames negative. Other safety factors (e.g., hERG, CYP inhibition, potential for drug-drug interactions) were also broadly acceptable for 9, 26 which additionally satisfied such criteria as high stability, low cost of synthesis and suitability for once-per-day oral administration noted in the proposed target product profile for a VL drug. 58 Oral treatment for VL offers many important advantages, including convenience and improved patient compliance; it also enables direct delivery of the absorbed drug to the liver, a major parasite population site.…”

“…58 Oral treatment for VL offers many important advantages, including convenience and improved patient compliance; it also enables direct delivery of the absorbed drug to the liver, a major parasite population site. 26 Therefore, the repositioning of 9…”