Linking murine and human Plasmodium falciparum challenge models in a translational path for antimalarial drug development

McCarthy, James S., Marquart, Louise, Sekuloski, Silvana, Trenholme, Katherine, Elliott, Suzanne, Griffin, Paul, Rockett, Rebecca, O'Rourke, Peter, Sloots, Theo, Angulo-Barturen, Inigo, Ferrer, Santiago, Jimenez-Diaz, Maria Belen, Martinez, Maria-Santos, van Huijsduijnen, Rob Hoof, Duparc, Stephan, Leroy, Didier, Wells, Timothy N. C., Baker, Mark and Mohrle, Jorg J. (2016) Linking murine and human Plasmodium falciparum challenge models in a translational path for antimalarial drug development. Antimicrobial Agents and Chemotherapy, 60 6: 3669-3675. doi:10.1128/AAC.02883-15


Author McCarthy, James S.
Marquart, Louise
Sekuloski, Silvana
Trenholme, Katherine
Elliott, Suzanne
Griffin, Paul
Rockett, Rebecca
O'Rourke, Peter
Sloots, Theo
Angulo-Barturen, Inigo
Ferrer, Santiago
Jimenez-Diaz, Maria Belen
Martinez, Maria-Santos
van Huijsduijnen, Rob Hoof
Duparc, Stephan
Leroy, Didier
Wells, Timothy N. C.
Baker, Mark
Mohrle, Jorg J.
Title Linking murine and human Plasmodium falciparum challenge models in a translational path for antimalarial drug development
Formatted title
Linking murine and human Plasmodium falciparum challenge models in a translational path for antimalarial drug development
Journal name Antimicrobial Agents and Chemotherapy   Check publisher's open access policy
ISSN 1098-6596
Publication date 2016-06
Year available 2016
Sub-type Article (original research)
DOI 10.1128/AAC.02883-15
Open Access Status DOI
Volume 60
Issue 6
Start page 3669
End page 3675
Total pages 7
Place of publication Washington, DC United States
Publisher American Society for Microbiology
Collection year 2017
Language eng
Formatted abstract
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 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 μg/ml and 1.8 μg/ml in the NSG and IBSM models, respectively, aligning with 1.8 μg/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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

 
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Created: Mon, 25 Apr 2016, 11:24:12 EST by Paul Griffin on behalf of Medicine - Mater Hospital