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Preclinical antimalarial combination studies: the case of M5717, a P. falciparum elongation factor 2 inhibitor and pyronaridine, a hemozoin formation inhibitor

Rottmann, Matthias and Jonat, Brian and Gumpp, Christin and Dhingra, Satish K. and Giddins, Marla J. and Yin, Xiaoyan and Badolo, Lassina and Greco, Beatrice and Fidock, David A. and Oeuvray, Claude and Spangenberg, Thomas. (2020) Preclinical antimalarial combination studies: the case of M5717, a P. falciparum elongation factor 2 inhibitor and pyronaridine, a hemozoin formation inhibitor. Antimicrobial agents and chemotherapy, 64 (4). e02181-19.

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Abstract

Antimalarial drug resistance in the; Plasmodium falciparum; parasite poses a constant challenge for drug development. To mitigate this risk, new antimalarial medicines should be developed as fixed-dose combinations. Assessing the pharmacodynamic interactions of potential antimalarial drug combination partners during early phases of development is essential in developing the targeted parasitological and clinical profile of the final drug product. Here, we have studied the combination of M5717, a; P. falciparum; translation elongation factor 2 inhibitor, and pyronaridine, an inhibitor of hemozoin formation. Our test cascade consisted of; in vitro; isobolograms as well as; in vivo; studies in the; P. falciparum; severe combined immunodeficient (SCID) mouse model. We also analyzed pharmacokinetic and pharmacodynamic parameters, including genomic sequencing of recrudescent parasites. We observed no pharmacokinetic interactions with the combination of M5717 and pyronaridine. M5717 did not negatively impact the rate of kill of the faster-acting pyronaridine, and the latter was able to suppress the selection of M5717-resistant mutants, as well as significantly delay the recrudescence of parasites both with suboptimal and optimal dosing regimens.
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:Rottmann, Matthias and Gumpp, Christin
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Society for Microbiology
ISSN:0066-4804
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
Identification Number:
Last Modified:27 Mar 2020 08:54
Deposited On:27 Mar 2020 08:54

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