Fractional curative killing of pyronaridine or artesunate combinations with tafenoquine, 4-aminoquinolines, or azithromycin in a murine malaria-luciferase model.

Abstract

Malaria drug interactions in cytostatic or inhibitory in vitro assays or suppression models in vivo can be different than curative killing interactions. In the pharmacodynamic high parasitemia Plasmodium berghei ANKA-luciferase mouse blood-stage model, we investigated curative interaction analysis of multiple, daily dosed, short half-life, artesunate or single-dose, long half-life, pyronaridine against three single-dose, long half-life, quinolines-chloroquine, amodiaquine, and tafenoquine. Positive or negative parasiticidal activity measured by parasite reduction rate in the days post-treatment correlated nonspecifically to final curative interactions. Tafenoquine/artesunate and pyronaridine/amodiaquine also had fractional combination curative doses of 0.83 and 0.93, with the rest of the interactions closer to neutral at 0.9-1.1. All tested combinations are in the additive drug interaction range. Time to return of initial parasitemia in subcurative regimens was also imprecise for the prediction of cure with combinations. Short blood half-life azithromycin, requiring multiple daily doses, was additive to artesunate or pyronaridine in fractional curative dose combination killing. Murine malaria high parasitemia drug interactions at the curative metric in vivo are a potential benchmark for human studies.