Towards clinically relevant dose ratios for Cabamiquine and Pyronaridine combination using P. falciparum field isolate data
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.
Authors
- Claude Oeuvray
- Yacouba N. Barre
- Fanta Sogore
- Abdoulaye Djimdé (ORCID: https://orcid.org/0000-0003-0062-2283)
- François Dao (ORCID: https://orcid.org/0000-0003-4925-6093)
- Fatoumata O. Maiga
- Sékou Sissoko (ORCID: https://orcid.org/0000-0002-8390-1431)
- Antoine Dara (ORCID: https://orcid.org/0000-0002-7739-4437)
- Ousmaila Diakité
- Laurent Dembélé (ORCID: https://orcid.org/0000-0001-9087-8439)
- Claudia Demarta‐Gatsi (ORCID: https://orcid.org/0000-0002-9610-2962)
- Sebastian G. Wicha (ORCID: https://orcid.org/0000-0002-8773-4845)
- Akash Khandelwal (ORCID: https://orcid.org/0000-0002-0472-7173)
- Thomas Spangenberg (ORCID: https://orcid.org/0000-0002-5654-8919)
- Mohamed Maïga (ORCID: https://orcid.org/0000-0003-1537-9087)
- Seidina A. S. Diakité (ORCID: https://orcid.org/0000-0003-1193-6501)
- Perrine Courlet (ORCID: https://orcid.org/0000-0001-9114-7793)
- Mahamadou Diakité (ORCID: https://orcid.org/0000-0002-4268-8857)
- Siaka Goïta
Institutions
- Universität Hamburg (DE)
- Merck KGaA, Darmstadt (Germany) (DE)
- Institut d'Économie Rurale (ML)
- Université des Sciences, des Techniques et des Technologies de Bamako (ML)
- Merck Serono S.A. (Switzerland) (CH)
- Hamburg Institut (Germany) (DE)
- UCB Pharma (Germany) (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-09-03
- DOI
- https://doi.org/10.1038/s41467-024-51994-3
- Citations
- 2
- Primary Topic
- Malaria Research and Control
- Type
- article
- Field-Weighted Citation Impact
- 1.09
Funders
- Merck KGaA