Towards clinically relevant dose ratios for Cabamiquine and Pyronaridine combination using P. falciparum field isolate data

Mohamed Maiga, Laurent Dembele (), Perrine Courlet, Akash Khandelwal, Antoine Dara, Fanta Sogore, Ousmaila Diakité, Fatoumata O. Maiga, François Dao, Sekou Sissoko, Yacouba Barre, Siaka Goita, Mahamadou Diakite, Seidina A. S. Diakite, Abdoulaye A. Djimde, Claude Oeuvray, Thomas Spangenberg, Sebastian G. Wicha () and Claudia Demarta-Gatsi ()
Additional contact information
Mohamed Maiga: Faculty of Pharmacy
Laurent Dembele: Faculty of Pharmacy
Perrine Courlet: Merck Institute of Pharmacometrics (an affiliate of Merck KGaA)
Akash Khandelwal: The Healthcare Business of Merck KGaA
Antoine Dara: Faculty of Pharmacy
Fanta Sogore: Faculty of Pharmacy
Ousmaila Diakité: Faculty of Pharmacy
Fatoumata O. Maiga: Faculty of Pharmacy
François Dao: Faculty of Pharmacy
Sekou Sissoko: Faculty of Pharmacy
Yacouba Barre: Faculty of Pharmacy
Siaka Goita: Faculty of Pharmacy
Mahamadou Diakite: Faculty of Pharmacy
Seidina A. S. Diakite: Faculty of Pharmacy
Abdoulaye A. Djimde: Faculty of Pharmacy
Claude Oeuvray: Global Health R&D of the healthcare business of Merck KGaA, Darmstadt, Germany, Ares Trading S.A. (an affiliate of Merck KGaA, Darmstadt, Germany)
Thomas Spangenberg: Global Health R&D of the healthcare business of Merck KGaA, Darmstadt, Germany, Ares Trading S.A. (an affiliate of Merck KGaA, Darmstadt, Germany)
Sebastian G. Wicha: University of Hamburg
Claudia Demarta-Gatsi: Pathogens genomic Diversity Network Africa, Sotuba

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: Abstract The selection and combination of dose regimens for antimalarials involve complex considerations including pharmacokinetic and pharmacodynamic interactions. In this study, we use immediate ex vivo P. falciparum field isolates to evaluate the effect of cabamiquine and pyronaridine as standalone treatments and in combination therapy. We feed the data into a pharmacometrics model to generate an interaction map and simulate meaningful clinical dose ratios. We demonstrate that the pharmacometrics model of parasite growth and killing provides a detailed description of parasite kinetics against cabamiquine-susceptible and resistant parasites. Pyronaridine monotherapy provides suboptimal killing rates at doses as high as 720 mg. In contrast, the combination of a single dose of 330 mg cabamiquine and 360 mg pyronaridine provides over 90% parasite killing in most of the simulated patients. The described methodology that combines a rapid, 3R-compliant in vitro method and modelling to set meaningful doses for new antimalarials could contribute to clinical drug development.

Date: 2024
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DOI: 10.1038/s41467-024-51994-3

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