Artemisinin derivatives – the most effective and widely-used antimalarials that have helped reduce the burden of falciparum malaria by 60% in some areas over the past decade – have recently been found to induce growth retardation of blood-stage Plasmodium falciparum when applied at clinically relevant concentrations.
To date, no model has been designed to quantify the growth retardation effect and to predict the influence of this property on in vivo parasite killing. Here we introduce a mechanistic model of parasite growth from the ring to trophozoite stage of the parasite’s life cycle, and by modelling the level of staining with an RNA-binding dye, we demonstrate that the model is able to reproduce fluorescence distribution data from in vitro experiments using the laboratory 3D7 strain.
We quantify the dependence of growth retardation on drug concentration and identify the concentration threshold above which growth retardation is evident. We estimate that the parasite life cycle is prolonged by up to 10 hours and illustrate that even such a relatively short delay in growth may significantly influence in vivo parasite dynamics. Given the stage sensitivity of the parasite to drug and the short half-life of the artemisinin derivatives in vivo, growth retardation may therefore manifest as drug resistance whereby the parasite simply outlasts the drug before continuing to mature.
Our findings will contribute to the interpretation of in vitro assay data on drug activity, demonstrate that growth retardation should be considered during the design of optimal artemisinin-based dosing regimens, and reinforce the importance for developing new antimalarial drugs with a longer in vivo half-life compared to the artemisinins.