Details

Autor(en) / Beteiligte

• Birrell, Geoffrey W
• Heffernan, Gavin D
• Schiehser, Guy A
• Anderson, John
• Ager, Arba L
• Morales, Pablo
• MacKenzie, Donna
• van Breda, Karin
• Chavchich, Marina
• Jacobus, Laura R
• Shanks, G Dennis
• Jacobus, David P
• Edstein, Michael D

Titel

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

Ist Teil von

• Antimicrobial agents and chemotherapy, 2018-04, Vol.62 (4)

Ort / Verlag

United States: American Society for Microbiology

Erscheinungsjahr

2018

Quelle

EZB Free E-Journals

Beschreibungen/Notizen

• The new 2-aminomethylphenol, JPC-3210, has potent antimalarial activity against multidrug-resistant lines, low cytotoxicity, and high efficacy against murine malaria. Here we report on the pharmacokinetics of JPC-3210 in mice and monkeys and the results of 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 -infected mice than in healthy mice. 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. 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 potency have led the Medicines for Malaria Venture to select JPC-3210 (MMV892646) for further advanced preclinical development.