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

Artemisinin resistance constitutes a major threat to the continued success of control programs for malaria, particularly in light of developing resistance to partner drugs. Improving our understanding of how artemisinin-based drugs act and how resistance manifests is essential for the optimisation of dosing regimens and the development of strategies to prolong the lifespan of current first-line treatment options. Recent short drug-pulse in vitro experiments have shown that the parasite killing rate depends not only on drug concentration but also the exposure time, challenging the standard pharmacokinetic-pharmacodynamic(PK-PD) paradigm in which the killing rate depends only on drug concentration. Here we introduce a "dynamic stress" model of parasite killing and show through application to 3D7 laboratory strain viability data that the inclusion of a time-dependent parasite stress response dramatically improves the model's explanatory power compared to a traditional PK-PD model. Our model demonstrates that the previously reported hypersensitivity of early ring stage parasites of the 3D7 strain to dihydroartemisinin compared to other parasite stages is primarily due to a faster development of stress, rather than a higher maximum achievable killing rate. We also perform in vivo simulations using the dynamic stress model and demonstrate that the complex temporal features of artemisinin action observed in vitro have a significant impact on predictions for in vivo parasite clearance. Given the important role that PK-PD models play in the design of clinical trials for the evaluation of alternative drug dosing regimens, our novel model will contribute to the further development and improvement of antimalarial therapies.

http://ift.tt/2yVKtXT