  Artemisinin resistance constitutes a major threat to the continued success of
control programs for malaria. With alternative antimalarial drugs not yet
available, improving our understanding of how artemisinin-based drugs act and
how resistance manifests is essential to enable optimisation of dosing regimens
in 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 to
maintain efficacy and how artemisinin resistance may manifest and be overcome.
We introduce a dynamic mathematical model, extending on the traditional
pharmacokinetic-pharmacodynamic framework, to capture the time-dependent
development of a stress response in parasites. We fit the model to in vitro
data and establish that the parasites' stress response explains the recently
identified complex interplay between drug concentration, exposure time and
parasite viability. Our model demonstrates that the previously reported
hypersensitivity of early ring stage parasites of the 3D7 strain to
dihydroartemisinin (DHA) is primarily due to the rapid development of stress,
rather than any change in the maximum achievable killing rate. Of direct
clinical relevance, we demonstrate that the complex temporal features of
artemisinin action observed in vitro have a significant impact on predictions
of in vivo parasite clearance using PK-PD models. Given the important role that
such models play in the design and evaluation of clinical trials for
alternative drug dosing regimens, our model contributes an enhanced predictive
platform for the continued efforts to minimise the burden of malaria.
