Abstract
Ensuring continued success against malaria depends on a pipeline of new antimalarials. Antimalarial drug development utilizes preclinical murine and experimental human malaria infection studies to evaluate drug efficacy. A sequential approach is typically adapted, with results from each stage informing the design of the next stage of development. The validity of this approach depends on confidence that results from murine malarial studies predict the outcome of clinical trials in humans. Parasite clearance rates following treatment are key parameters of drug efficacy. To investigate the validity of forward predictions, we developed a suite of mathematical models to capture parasite growth and drug clearance along the drug development pathway and estimated parasite clearance rates. When comparing the three infection experiments, we identified different relationships of parasite clearance with dose and different maximum parasite clearance rates. In Plasmodium berghei-NMRI mouse infections, we estimated a maximum parasite clearance rate of 0.2 (1/h); in Plasmodium falciparum-SCID mouse infections, 0.05 (1/h); and in human volunteer infection studies with P. falciparum, we found a maximum parasite clearance rate of 0.12 (1/h) and 0.18 (1/h) after treatment with OZ439 and MMV048, respectively. Sensitivity analysis revealed that host-parasite driven processes account for up to 25% of variance in parasite clearance for medium-high doses of antimalarials. Although there are limitations in translating parasite clearance rates across these experiments, they provide insight into characterizing key parameters of drug action and dose response and assist in decision-making regarding dosage for further drug development.
Highlights
Introduction and BackgroundRecent progress in reducing malaria burden is threatened by emerging resistance against current first-line treatments and by sub-optimal adherence to existing treatment schedules
The design of the studies/experiments used to evaluate the candidate antimalarials (MMV048 and OZ439) in normal mice, scidIL-2R' c-/- (SCID) mice and human volunteers is described in Table 1 and Fig. 2
Mice were infected with around 2x107 parasites or greater inocula resulting in progression to severe disease with high parasitemia of up to 60-80 % (P. berghei, parasitized mouse red blood cells (RBC)) and 15-20 % (P. falciparum, parasitized human RBCs) within a week of inoculation
Summary
Recent progress in reducing malaria burden is threatened by emerging resistance against current first-line treatments and by sub-optimal adherence to existing treatment schedules. Development of new antimalarial treatments is more urgent than ever [1]. Requirements for new antimalarial treatment regimens are multi-facetted, spanning safety, efficacy, and dose optimization for all populations, including pregnant women, infants and children [2]. Infection of normal mice with P. berghei was shown to be a useful experiment to measure crude drug efficacy and to select promising candidates [4]. Enzymatic differences between the human malaria parasite P. falciparum led to selection bias in candidate selection [5]. The humanized mouse model of NOD scidIL-2R' c-/- (SCID) mice infected with P
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
