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
; 65: 147-55, 2014 Dec 18.
Article
in En
| MEDLINE
| ID: mdl-25261338
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Leishmaniasis, Visceral
/
Antiparasitic Agents
Type of study:
Prognostic_studies
/
Risk_factors_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Eur J Pharm Sci
Journal subject:
FARMACIA
/
FARMACOLOGIA
/
QUIMICA
Year:
2014
Document type:
Article
Affiliation country:
India