Superior Pyronaridine Single Dose Pharmacodynamics Compared to Artesunate, Chloroquine and Amodiaquine In A Murine Malaria-Luciferase Model [PublishAheadOfPrint]

Many previous in vitro and in vivo preclinical malaria drug studies have relied on low parasite number drug inhibition numerically compared to untreated controls. In contrast, human malaria drug studies measure the high parasite density killing near 100 million/mL. Here we compared the in vivo single dose pharmacodynamic properties of artesunate and 4-aminoquinolines-pyronaridine, chloroquine, and amodiaquine, in a Plasmodium bergheiANKA-GFP-Luciferase-based murine malaria blood stage model. Pyronaridine exhibited dose-dependent killing, achieving parasite reduction near 5-6 logs at 48 hours with complete cure at 10 mg/kg compared to artesunate, which exhibited a 48 hour dose-dependent killing with a 2 log drop at the noncurative 250 mg/kg dose. Chloroquine, noncurative, and amodiaquine, partially curative, have nearly the same initial dose-independent killing with a lag phase of minimal parasite reduction at all doses between 6 and 24 hours, followed by 2.5 log reduction at 48 hours. In drug treated, washed infected blood transfer experiments to naïve mice, chloroquine and amodiaquine showed less viable parasites at the 24 hour compared to 8 hour transfer measured by a prolonged return to parasitemia, despite a similar parasite log reduction at these time points, in contrast to the correlation of parasite log reduction to viable parasites with artesunate and pyronaridine. Artesunate in combination with pyronaridine exhibited a similar initial parasite reduction to pyronaridine, while with chloroquine or amodiaquine, the reduction was similar to artesunate. Single oral dose pyronaridine was much more potent in vivo than artesunate, chloroquine and amodiaquine during the initial decline in parasites and cure.

https://ift.tt/2KEVq9K