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

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

Author information

1
Advinus Therapeutics Ltd., Bangalore, India.
2
Drugs for Neglected Diseases Initiative, Geneva, Switzerland.
3
Drugs for Neglected Diseases Initiative, Geneva, Switzerland. Electronic address: dmartin@dndi.org.

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

PMID:
25261338
DOI:
10.1016/j.ejps.2014.09.006
[Indexed for MEDLINE]
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