RT Journal Article
T1 Linking murine and human Plasmodium falciparum challenge models in a translational path for antimalarial drug development
A1 Ferrer Bazaga, Santiago
AB Effective progression of candidate antimalarials is dependent on optimal dosing in clinical studies, which is determined by a sound understanding of pharmacokinetics and pharmacodynamics (PK/PD). Recently, two important translational models for antimalarials have been developed: the NOD/SCID/IL2Rgamma−/− (NSG) model, whereby mice are engrafted with noninfected and Plasmodium falciparum-infected human erythrocytes, and the induced blood-stage malaria (IBSM) model in human volunteers. The antimalarial mefloquine was used to directly measure the PK/PD in both models, which were compared to previously published trial data for malaria patients. The clinical part was a single-center, controlled study using a blood-stage Plasmodium falciparum challenge inoculum in volunteers to characterize the effectiveness of mefloquine against early malaria. The study was conducted in three cohorts (n = 8 each) using different doses of mefloquine. The characteristic delay in onset of action of about 24 h was seen in both NSG and IBSM systems. In vivo 50% inhibitory concentrations (IC50s) were estimated at 2.0 mug/ml and 1.8 mug/ml in the NSG and IBSM models, respectively, aligning with 1.8 mug/ml reported previously for patients. In the IBSM model, the parasite reduction ratios were 157 and 195 for the 10- and 15-mg/kg doses, within the range of previously reported clinical data for patients but significantly lower than observed in the mouse model. Linking mouse and human challenge models to clinical trial data can accelerate the accrual of critical data on antimalarial drug activity. Such data can guide large clinical trials required for development of urgently needed novel antimalarial combinations.
PB American Society for Microbiology
SN 0066-4804
YR 2016
FD 2016-06-01
LK https://hdl.handle.net/10016/38815
UL https://hdl.handle.net/10016/38815
LA eng
NO This work, including the efforts of James S. McCarthy, was funded byAustralian National Health and Medical Research Council. This work,including the efforts of Timothy Wells, was funded by Wellcome Trust(095909/Z/11/Z).
DS e-Archivo
RD 30 jun. 2024