Characterization of the Preclinical Pharmacology of the New 2-Aminomethylphenol, JPC-3210, for Malaria Treatment and Prevention.

Autor:	Birrell GW; Department of Drug Evaluation, Australian Army Malaria Institute (AMI), Brisbane, Queensland, Australia., Heffernan GD; Jacobus Pharmaceutical Company, Princeton, New Jersey, USA., Schiehser GA; Jacobus Pharmaceutical Company, Princeton, New Jersey, USA., Anderson J; Jacobus Pharmaceutical Company, Princeton, New Jersey, USA., Ager AL; University of Miami, Miami, Florida, USA., Morales P; Mannheimer Foundation, Inc., Homestead, Florida, USA., MacKenzie D; Department of Drug Evaluation, Australian Army Malaria Institute (AMI), Brisbane, Queensland, Australia., van Breda K; Department of Drug Evaluation, Australian Army Malaria Institute (AMI), Brisbane, Queensland, Australia., Chavchich M; Department of Drug Evaluation, Australian Army Malaria Institute (AMI), Brisbane, Queensland, Australia., Jacobus LR; Jacobus Pharmaceutical Company, Princeton, New Jersey, USA., Shanks GD; Department of Drug Evaluation, Australian Army Malaria Institute (AMI), Brisbane, Queensland, Australia., Jacobus DP; Jacobus Pharmaceutical Company, Princeton, New Jersey, USA., Edstein MD; Department of Drug Evaluation, Australian Army Malaria Institute (AMI), Brisbane, Queensland, Australia Mike.Edstein@defence.gov.au.
Jazyk:	angličtina
Zdroj:	Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2018 Mar 27; Vol. 62 (4). Date of Electronic Publication: 2018 Mar 27 (Print Publication: 2018).
DOI:	10.1128/AAC.01335-17
Abstrakt:	The new 2-aminomethylphenol, JPC-3210, has potent in vitro antimalarial activity against multidrug-resistant Plasmodium falciparum lines, low cytotoxicity, and high in vivo efficacy against murine malaria. Here we report on the pharmacokinetics of JPC-3210 in mice and monkeys and the results of in vitro screening assays, including the inhibition of cytochrome P450 (CYP450) isozymes. In mice, JPC-3210 was rapidly absorbed and had an extensive tissue distribution, with a brain tissue-to-plasma concentration ratio of about 5.4. JPC-3210 had a lengthy plasma elimination half-life of about 4.5 days in mice and 11.8 days in monkeys. JPC-3210 exhibited linear single-oral-dose pharmacokinetics across the dose range of 5 to 40 mg/kg of body weight with high oral bioavailability (∼86%) in mice. Systemic blood exposure of JPC-3210 was 16.6% higher in P. berghei -infected mice than in healthy mice. In vitro studies with mice and human hepatocytes revealed little metabolism and the high metabolic stability of JPC-3210. The abundance of human metabolites from oxidation and glucuronidation was 2.0% and 2.5%, respectively. CYP450 studies in human liver microsomes showed JPC-3210 to be an inhibitor of CYP2D6 and, to a lesser extent, CYP3A4 isozymes, suggesting the possibility of a metabolic drug-drug interaction with drugs that are metabolized by these isozymes. In vitro studies showed that JPC-3210 is highly protein bound to human plasma (97%). These desirable pharmacological findings of a lengthy blood elimination half-life, high oral bioavailability, and low metabolism as well as high in vivo potency have led the Medicines for Malaria Venture to select JPC-3210 (MMV892646) for further advanced preclinical development. (© Crown copyright 2018.)
Databáze:	MEDLINE
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