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 (10 μM) and was highly permeable (>200 nm/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 (

Citation

Mukkavilli, R.; Pinjari, J.; Patel, B.; Sengottuvelan, S.; Mondal, S.; Gadekar, A.; Verma, M.; Patel, J.; Pothuri, L.; Chadrashekar, G.; Koiram, P.; Harisudhan, T.; Moinuddin, A.; Launay, D.; Vachharajani, N.; Ramanathan, V.; Martin, D. In vitro metabolism, disposition, preclinical pharmacokinetics and prediction of human pharmacokinetics of DNDI-VL-2098, a potential oral treatment for Visceral Leishmaniasis. European Journal of Pharmaceutical Sciences (2014) 65: 147-155. [DOI: 10.1016/j.ejps.2014.09.006]

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

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