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Parasite viability as a measure of in vivo drug activity in preclinical and early clinical antimalarial drug assessment

Radohery, G. F. R. and Walz, A. and Gumpp, C. and Cherkaoui-Rbati, M. H. and Gobeau, N. and Gower, J. and Davenport, M. P. and Rottmann, M. and McCarthy, J. S. and Möhrle, J. J. and Rebelo, M. and Demarta-Gatsi, C. and Khoury, D. S.. (2022) Parasite viability as a measure of in vivo drug activity in preclinical and early clinical antimalarial drug assessment. Antimicrob Agents Chemother, 66 (7). e0011422.

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Abstract

The rate at which parasitemia declines in a host after treatment with an antimalarial drug is a major metric for assessment of antimalarial drug activity in preclinical models and in early clinical trials. However, this metric does not distinguish between viable and nonviable parasites. Thus, enumeration of parasites may result in underestimation of drug activity for some compounds, potentially confounding its use as a metric for assessing antimalarial activity in vivo. Here, we report a study of the effect of artesunate on Plasmodium falciparum viability in humans and in mice. We first measured the drug effect in mice by estimating the decrease in parasite viability after treatment using two independent approaches to estimate viability. We demonstrate that, as previously reported in humans, parasite viability declines much faster after artesunate treatment than does the decline in parasitemia (termed parasite clearance). We also observed that artesunate kills parasites faster at higher concentrations, which is not discernible from the traditional parasite clearance curve and that each subsequent dose of artesunate maintains its killing effect. Furthermore, based on measures of parasite viability, we could accurately predict the in vivo recrudescence of infection. Finally, using pharmacometrics modeling, we show that the apparent differences in the antimalarial activity of artesunate in mice and humans are partly explained by differences in host removal of dead parasites in the two hosts. However, these differences, along with different pharmacokinetic profiles, do not fully account for the differences in activity. (This study has been registered with the Australian New Zealand Clinical Trials Registry under identifier ACTRN12617001394336.).
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 Medical Parasitology and Infection Biology (MPI) > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Walz, Annabelle and Gumpp, Christin and Rottmann, Matthias
Item Type:Article, refereed
Article Subtype:Research Article
ISSN:1098-6596 (Electronic)0066-4804 (Linking)
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
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Last Modified:27 Dec 2022 21:06
Deposited On:27 Dec 2022 21:06

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