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Ensemble modeling highlights importance of understanding parasite-host behavior in preclinical antimalarial drug development

Burgert, Lydia and Rottmann, Matthias and Wittlin, Sergio and Gobeau, Nathalie and Krause, Andreas and Dingemanse, Jasper and Möhrle, Jörg J. and Penny, Melissa A.. (2020) Ensemble modeling highlights importance of understanding parasite-host behavior in preclinical antimalarial drug development. Scientific reports, 10. p. 4410.

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Official URL: https://edoc.unibas.ch/76103/

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Abstract

Emerging drug resistance and high-attrition rates in early and late stage drug development necessitate accelerated development of antimalarial compounds. However, systematic and meaningful translation of drug efficacy and host-parasite dynamics between preclinical testing stages is missing. We developed an ensemble of mathematical within-host parasite growth and antimalarial action models, fitted to extensive data from four antimalarials with different modes of action, to assess host-parasite interactions in two preclinical drug testing systems of murine parasite P. berghei in mice, and human parasite P. falciparum in immune-deficient mice. We find properties of the host-parasite system, namely resource availability, parasite maturation and virulence, drive P. berghei dynamics and drug efficacy, whereas experimental constraints primarily influence P. falciparum infection and drug efficacy. Furthermore, uninvestigated parasite behavior such as dormancy influences parasite recrudescence following non-curative treatment and requires further investigation. Taken together, host-parasite interactions should be considered for meaningful translation of pharmacodynamic properties between murine systems and for predicting human efficacious treatment.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Epidemiology and Public Health (EPH) > Disease Dynamics > Disease and Intervention (Penny)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Burgert, Lydia and Rottmann, Matthias and Wittlin, Sergio and Penny, Melissa
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Springer Nature
ISSN:0169-5487
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
Identification Number:
Last Modified:27 Mar 2020 06:54
Deposited On:27 Mar 2020 06:54

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