Metabolic, Pharmacokinetic, and Activity Profile of the Liver Stage Antimalarial (RC-12)

Abstract

The catechol derivative RC-12 (WR 27653) ( 1 ) is one of the few non-8-aminoquinolines with good activity against hypnozoites in the gold-standard Plasmodium cynomolgi –rhesus monkey ( Macaca mulatta ) model, but in a small clinical trial, it had no efficacy against Plasmodium vivax hypnozoites. In an attempt to better understand the pharmacokinetic and pharmacodynamic profile of 1 and to identify potential active metabolites, we now describe the phase I metabolism, rat pharmacokinetics, and in vitro liver-stage activity of 1 and its metabolites. Compound 1 had a distinct metabolic profile in human vs monkey liver microsomes, and the data suggested that the O -desmethyl, combined O -desmethyl/ N -desethyl, and N,N -didesethyl metabolites (or a combination thereof) could potentially account for the superior liver stage antimalarial efficacy of 1 in rhesus monkeys vs that seen in humans. Indeed, the rate of metabolism was considerably lower in human liver microsomes in comparison to rhesus monkey microsomes, as was the formation of the combined O -desmethyl/ N -desethyl metabolite, which was the only metabolite tested that had any activity against liver-stage P. vivax ; however, it was not consistently active against liver-stage P. cynomolgi . As 1 and all but one of its identified Phase I metabolites had no in vitro activity against P. vivax or P. cynomolgi liver-stage malaria parasites, we suggest that there may be additional unidentified active metabolites of 1 or that the exposure of 1 achieved in the reported unsuccessful clinical trial of this drug candidate was insufficient to kill the P. vivax hypnozoites.

A Drug Repurposing Approach Reveals Targetable Epigenetic Pathways inPlasmodium vivaxHypnozoites

“…This report also provides an opportunity to compare radical cure hits assayed against both P. vivax and P. cynomolgi hypnozoites. While the P. cynomolgi-infected rhesus macaque system has long been used as a model system for studying malaria relapse, the only class of compounds available to assess the predictive value of this model for chemotherapeutics are the 8-aminoquinolines, which lack a distinct parasite target (22)(23)(24)(25). We found mixed results, with hydrazinophthalazines negative, and poziotinib positive, against P. cynomolgi hypnozoites.…”

“…Instead, they were discovered using animal models, including the P. cynomolgi-infected rhesus macaque system 12 . The 8-aminoquionlines function through generation of reactive oxygen species affecting both the host and parasite, and lack a distinct parasite target [60][61][62][63] . As such, this work represents one of the first applications of a radical cure development pipeline to begin with in vitro screening against P. vivax hypnozoites and end with attempted confirmation using P. cynomolgi radical cure models.…”