title: 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 (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.
authors.affiliation: Advinus Therapeutics Ltd., Bangalore, India.
authors.forename: Rao
authors.initials: R
authors.lastname: Mukkavilli
authors.affiliation: Advinus Therapeutics Ltd., Bangalore, India.
authors.forename: Jakir
authors.initials: J
authors.lastname: Pinjari
authors.affiliation: Advinus Therapeutics Ltd., Bangalore, India.
authors.forename: Bhavesh
authors.initials: B
authors.lastname: Patel
authors.affiliation: Advinus Therapeutics Ltd., Bangalore, India.
authors.forename: Shankar
authors.initials: S
authors.lastname: Sengottuvelan
authors.affiliation: Advinus Therapeutics Ltd., Bangalore, India.
authors.forename: Subodh
authors.initials: S
authors.lastname: Mondal
authors.affiliation: Advinus Therapeutics Ltd., Bangalore, India.
authors.forename: Ajit
authors.initials: A
authors.lastname: Gadekar
authors.affiliation: Advinus Therapeutics Ltd., Bangalore, India.
authors.forename: Manas
authors.initials: M
authors.lastname: Verma
authors.affiliation: Advinus Therapeutics Ltd., Bangalore, India.
authors.forename: Jignesh
authors.initials: J
authors.lastname: Patel
authors.affiliation: Advinus Therapeutics Ltd., Bangalore, India.
authors.forename: Lavanya
authors.initials: L
authors.lastname: Pothuri
authors.affiliation: Advinus Therapeutics Ltd., Bangalore, India.
authors.forename: Gopu
authors.initials: G
authors.lastname: Chandrashekar
authors.affiliation: Advinus Therapeutics Ltd., Bangalore, India.
authors.forename: Prabhakar
authors.initials: P
authors.lastname: Koiram
authors.affiliation: Advinus Therapeutics Ltd., Bangalore, India.
authors.forename: Tanukrishnan
authors.initials: T
authors.lastname: Harisudhan
authors.affiliation: Advinus Therapeutics Ltd., Bangalore, India.
authors.forename: Ansari
authors.initials: A
authors.lastname: Moinuddin
authors.affiliation: Drugs for Neglected Diseases Initiative, Geneva, Switzerland.
authors.forename: Delphine
authors.initials: D
authors.lastname: Launay
authors.affiliation: Advinus Therapeutics Ltd., Bangalore, India.
authors.forename: Nimish
authors.initials: N
authors.lastname: Vachharajani
authors.affiliation: Advinus Therapeutics Ltd., Bangalore, India.
authors.forename: Vikram
authors.initials: V
authors.lastname: Ramanathan
authors.affiliation: Drugs for Neglected Diseases Initiative, Geneva, Switzerland. Electronic address: dmartin@dndi.org.
authors.forename: Denis
authors.initials: D
authors.lastname: Martin
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000977:Antiparasitic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001682:Biological Availability; D018938:Caco-2 Cells; D006224:Cricetinae; D004285:Dogs; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006207:Half-Life; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007898:Leishmaniasis, Visceral / Q000188:drug therapy*; D008099:Liver / Q000378:metabolism; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats
chemical_list: D000977:Antiparasitic Agents
keywords: Allometric scaling; Bioanalysis; Bioavailability; Cytochrome P450; Preclinical pharmacokinetics