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

Author

Listed:
  • 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
    Rolf-Schwarz-Schütte-Platz 1)

  • 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
    Pathogens genomic Diversity Network Africa, Sotuba)

  • 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
    Global Health R&D of the healthcare business of Merck KGaA, Darmstadt, Germany, Ares Trading S.A. (an affiliate of Merck KGaA, Darmstadt, Germany))

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.

Suggested Citation

  • 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 , 2024. "Towards clinically relevant dose ratios for Cabamiquine and Pyronaridine combination using P. falciparum field isolate data," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51994-3
    DOI: 10.1038/s41467-024-51994-3
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    References listed on IDEAS

    as
    1. Eva Stadler & Mohamed Maiga & Lukas Friedrich & Vandana Thathy & Claudia Demarta-Gatsi & Antoine Dara & Fanta Sogore & Josefine Striepen & Claude Oeuvray & Abdoulaye A. Djimdé & Marcus C. S. Lee & Lau, 2023. "Propensity of selecting mutant parasites for the antimalarial drug cabamiquine," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    2. Eva Stadler & Mohamed Maiga & Lukas Friedrich & Vandana Thathy & Claudia Demarta-Gatsi & Antoine Dara & Fanta Sogore & Josefine Striepen & Claude Oeuvray & Abdoulaye A. Djimdé & Marcus C. S. Lee & Lau, 2023. "Author Correction: Propensity of selecting mutant parasites for the antimalarial drug cabamiquine," Nature Communications, Nature, vol. 14(1), pages 1-1, December.
    3. Sebastian G. Wicha & Chunli Chen & Oskar Clewe & Ulrika S. H. Simonsson, 2017. "A general pharmacodynamic interaction model identifies perpetrators and victims in drug interactions," Nature Communications, Nature, vol. 8(1), pages 1-11, December.
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