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Artemisinin resistance constitutes a major threat to the continued success ofcontrol programs for malaria. With alternative antimalarial drugs not yetavailable, improving our understanding of how artemisinin-based drugs act andhow resistance manifests is essential to enable optimisation of dosing regimensin order to prolong the lifespan of current first-line treatment options. Here,through introduction of a novel model of the dynamics of the parasites'response to drug, we explore how artemisinin-based therapies may be adjusted tomaintain efficacy and how artemisinin resistance may manifest and be overcome.We introduce a dynamic mathematical model, extending on the traditionalpharmacokinetic-pharmacodynamic framework, to capture the time-dependentdevelopment of a stress response in parasites. We fit the model to in vitrodata and establish that the parasites' stress response explains the recentlyidentified complex interplay between drug concentration, exposure time andparasite viability. Our model demonstrates that the previously reportedhypersensitivity of early ring stage parasites of the 3D7 strain todihydroartemisinin (DHA) is primarily due to the rapid development of stress,rather than any change in the maximum achievable killing rate. Of directclinical relevance, we demonstrate that the complex temporal features ofartemisinin action observed in vitro have a significant impact on predictionsof in vivo parasite clearance using PK-PD models. Given the important role thatsuch models play in the design and evaluation of clinical trials foralternative drug dosing regimens, our model contributes an enhanced predictiveplatform for the continued efforts to minimise the burden of malaria.

A dynamic stress model explains the delayed drug effect in artemisinin treatment of Plasmodium falciparum