The rate at which
parasitemia declines in a host
after treatment with an
antimalarial drug is a major metric for assessment of
antimalarial drug activity in preclinical models and in early clinical trials. However, this metric does not distinguish between viable and nonviable parasites. Thus, enumeration of parasites may result in underestimation of
drug activity for some compounds, potentially confounding its use as a metric for assessing
antimalarial activity in vivo. Here, we report a study of the effect of
artesunate on Plasmodium falciparum viability in humans and in mice. We first measured the
drug effect in mice by estimating the decrease in parasite viability
after treatment using two independent approaches to estimate viability. We demonstrate that, as previously reported in humans, parasite viability declines much faster after
artesunate treatment than does the decline in
parasitemia (termed parasite clearance). We also observed that
artesunate kills parasites faster at higher concentrations, which is not discernible from the traditional parasite clearance curve and that each subsequent dose of
artesunate maintains its killing effect. Furthermore, based on measures of parasite viability, we could accurately predict the in vivo recrudescence of
infection. Finally, using pharmacometrics modeling, we show that the apparent differences in the
antimalarial activity of
artesunate in mice and humans are partly explained by differences in host removal of dead parasites in the two hosts. However, these differences, along with different pharmacokinetic profiles, do not fully account for the differences in activity. (This study has been registered with the Australian New Zealand Clinical Trials Registry under identifier ACTRN12617001394336.).