Linking Murine and Human Plasmodium falciparum Challenge Models in a Translational Path for Antimalarial Drug Development

James S. McCarthy, Louise Marquart, Silvana Sekuloski, Katharine Trenholme, Suzanne Elliott, Paul Griffin, Rebecca Rockett, Peter O'Rourke, Theo Sloots, Iñigo Angulo-Barturen, Santiago Ferrer, María Belén Jiménez-Díaz, María-Santos Martínez, Rob Hooft van Huijsduijnen, Stephan Duparc, Didier Leroy, Timothy N. C. Wells, Mark Baker, Jörg J. Möhrle

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/IL2Rγ(-/-)(NSG) model whereby mice are engrafted with non-infected andP. falciparum-infected human erythrocytes, and the induced blood-stage malaria model (IBSM) in human volunteers. The antimalarial mefloquine was used to directly measure the PK/PD in both models and compared to previously published trial data in malaria patients. The clinical part was a single-center, controlled, study using a blood stagePlasmodium falciparumchallenge inoculum in volunteers to characterize the effectiveness of mefloquine against early malaria. The study was conducted in three cohorts (n= 8 in each) using different doses of mefloquine. The characteristic delay in onset of action of about 24 hours was seen in both NSG and IBSM systems.In vivoIC50s were estimated at 2.0 μg/ml and 1.8 μg/ml in the NSG and IBSM models respectively, aligning with 1.8 μg/ml reported previously in 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 earlier reported clinical data in patients, but significantly lower than that 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.