Optimization of Antimalarial Drug Regimens in a Cytocidal Murine Malaria Model

Statement of Problem: Although malaria is a preventable and curable disease, over 200 million cases and 400,000 deaths were reported in 2016, with the burden of disease borne predominantly by young African children. Substantial headway has been made against this deadly disease in the last decade; however, drug resistant parasites continue to pose a challenge to the progress. We hypothesized that the efficacy of antimalarial drugs, both current and pipeline, could be improved by optimizing the treatment regimen including factors such as dose, dosing schedule, and treatment duration. Methods: We adapted a transgenic Plasmodium berghei GFP-luciferase reporter parasite to develop a cytocidal murine model of malaria with quantification of parasites per µL in the range of 1,200,000 – 600. This cytocidal model was used to study the efficacy of antimalarial drug regimens. This model is superior to the prevalent suppression assays as it more accurately mimics treatment of human malaria in the field. We also evaluated the utility of an artesunate-resistant P. berghei SANA as a model for evaluating the efficacy of antimalarials against P. falciparum isolates exhibiting delayed clearance to the artemisinins. Results: Extending the duration of the artemisinins from 3 days to 6 days enhances the efficacy of artemisinin combination therapies suggesting multiple lifecycle drug exposure performs better than single cell cycle exposure. Increasing the dosing frequency of fosmidomycin and clindamycin from twice daily to three or four times daily enhances their efficacy, which is indicative of a time above minimum inhibition concentration killing pattern. P. berghei SANA shows promise as a model of the drug sensitivity of artemisinin tolerant parasites. Conclusions: Successful human drug regimens require three key considerations: the dose of the drug, the schedule or frequency with which the drug is dosed each day, and the duration of daily treatment. This work demonstrates that there is substantial room to improve the efficacy of antimalarial drug regimens. Developing a novel murine model of artemisinin-tolerant Plasmodium parasites will further accelerate the development of next-generation antimalarials and serve as a platform on which currently approved antimalarials can be evaluated and improved