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

Eur J Pharm Sci. 2014 Dec 18;65:147-55. doi: 10.1016/j.ejps.2014.09.006. Epub 2014 Sep 27.

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.

Keywords: Allometric scaling; Bioanalysis; Bioavailability; Cytochrome P450; Preclinical pharmacokinetics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Antiparasitic Agents / pharmacokinetics*
  • Antiparasitic Agents / pharmacology*
  • Biological Availability
  • Caco-2 Cells
  • Cricetinae
  • Dogs
  • Drug Evaluation, Preclinical / methods
  • Half-Life
  • Hepatocytes / metabolism
  • Humans
  • Leishmaniasis, Visceral / drug therapy*
  • Liver / metabolism
  • Mice
  • Microsomes, Liver / metabolism
  • Rats

Substances

  • Antiparasitic Agents