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

by Mukkavilli R, Pinjari J, Patel B, Sengottuvelan S, Mondal S, Gadekar A, Verma M, Patel J, Pothuri L, Chandrashekar G, Koiram P, Harisudhan T, Moinuddin A, Launay D, Vachharajani N, Ramanathan V, Martin D. European Journal of Pharmaceutical Sciences 2014, doi:10.1016/j.ejps.2014.09.006.

Summary: The in vitro metabolism and in vivo pharmacokinetic 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, was highly permeable, and stable in vitro with very slow, if any, metabolism of the compound in vivo. It showed satisfactory PK properties in animal models with a low blood clearance and a volume of distribution of about 3 times total body water, acceptable half-life and good oral bioavailability. Allometric scaling of the preclinical PK data to human gave a blood half-life of approximately 20 h suggesting that the compound could be a once-a-day drug. The minimum efficacious dose predicted for a 50 kg human was predicted as 150 mg and 300 mg, using efficacy results in the mouse and hamster, respectively.

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