Towards clinically relevant dose ratios for Cabamiquine and Pyronaridine combination using P. falciparum field isolate data.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
03 Sep 2024
03 Sep 2024
Historique:
received:
15
02
2024
accepted:
22
08
2024
medline:
4
9
2024
pubmed:
4
9
2024
entrez:
3
9
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 39227370
doi: 10.1038/s41467-024-51994-3
pii: 10.1038/s41467-024-51994-3
doi:
Substances chimiques
Antimalarials
0
pyronaridine
TD3P7Q3SG6
Naphthyridines
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
7659Subventions
Organisme : Merck KGaA
ID : 10.13039/10000995
Informations de copyright
© 2024. The Author(s).
Références
World Health Organization. WHO Malaria Report 2019. Malaria Report 2019 (WHO, 2019).
World Health Organization. WHO Malaria Report 2022 (WHO, 2022).
Uwimana, A. et al. Emergence and clonal expansion of in vitro artemisinin-resistant Plasmodium falciparum kelch13 R561H mutant parasites in Rwanda. Nat. Med. 26, 1602–1608 (2020).
doi: 10.1038/s41591-020-1005-2
pubmed: 32747827
pmcid: 7541349
van der Pluijm, R. W. et al. Determinants of dihydroartemisinin-piperaquine treatment failure in Plasmodium falciparum malaria in Cambodia, Thailand, and Vietnam: a prospective clinical, pharmacological, and genetic study. Lancet Infect. Dis. 19, 952–961 (2019).
doi: 10.1016/S1473-3099(19)30391-3
pubmed: 31345710
pmcid: 6715822
Flegg, J. A. et al. Spatiotemporal spread of Plasmodium falciparum mutations for resistance to sulfadoxine-pyrimethamine across Africa, 1990–2020. PLoS Comput. Biol. 18, e1010317 (2022).
doi: 10.1371/journal.pcbi.1010317
pubmed: 35951528
pmcid: 9371298
Singh Sidhu, A. B., Verdier-Pinard, D. & Fidock, D. A. Chloroquine resistance in Plasmodium falciparum malaria parasites conferred by pfcrt mutations. Science 298, 210–213 (2002).
Baragaña, B. et al. A novel multiple-stage antimalarial agent that inhibits protein synthesis. Nature 522, 315–320 (2015).
doi: 10.1038/nature14451
pubmed: 26085270
pmcid: 4700930
Chu, W.-Y. & Dorlo, T. P. C. Pyronaridine: a review of its clinical pharmacology in the treatment of malaria. J. Antimicrob. Chemother. 78, 2406–2418 (2023).
doi: 10.1093/jac/dkad260
pubmed: 37638690
pmcid: 10545508
Kurth, F., Bélard, S., Basra, A. & Ramharter, M. Pyronaridine-artesunate combination therapy for the treatment of malaria. Curr. Opin. Infect. Dis. 24, 564–569 (2011).
Rottmann, M. et al. Preclinical antimalarial combination study of M5717, a Plasmodium falciparum elongation factor 2 inhibitor, and pyronaridine, a hemozoin formation inhibitor. Antimicrob. Agents Chemother. 64, 10–1128 (2020).
Jiménez-Díaz, M. B. et al. Improved murine model of malaria using Plasmodium falciparum competent strains and non-myelodepleted NOD-scid IL2Rgammanull mice engrafted with human erythrocytes. Antimicrob. Agents Chemother. 53, 4533–4536 (2009).
doi: 10.1128/AAC.00519-09
pubmed: 19596869
pmcid: 2764183
McCarthy, J. S. et al. Safety, pharmacokinetics, and antimalarial activity of the novel Plasmodium eukaryotic translation elongation factor 2 inhibitor M5717: a first-in-human, randomised, placebo-controlled, double-blind, single ascending dose study and volunteer infection stu. Lancet Infect. Dis. 21, 1713–1724 (2021).
doi: 10.1016/S1473-3099(21)00252-8
pubmed: 34715032
pmcid: 8612936
White, J. et al. In vitro adaptation of Plasmodium falciparum reveal variations in cultivability. Malar. J. 15, 33 (2016).
doi: 10.1186/s12936-015-1053-0
pubmed: 26794408
pmcid: 4722725
Chaorattanakawee, S. et al. Attenuation of Plasmodium falciparum in vitro drug resistance phenotype following culture adaptation compared to fresh clinical isolates in Cambodia. Malar. J. 14, 486 (2015).
doi: 10.1186/s12936-015-1021-8
pubmed: 26626127
pmcid: 4667454
Brown, A. C. & Guler, J. L. From circulation to cultivation: Plasmodium in vivo versus in vitro. Trends Parasitol. 36, 914–926 (2020).
doi: 10.1016/j.pt.2020.08.008
pubmed: 32958385
Piel, L. et al. Experimental evolution links posttranscriptional regulation to Leishmania fitness gain. PLoS Pathog. 18, e1010375 (2022).
doi: 10.1371/journal.ppat.1010375
pubmed: 35294501
pmcid: 8959184
Lee, H. J. et al. Transcriptomic studies of malaria: a paradigm for investigation of systemic host-pathogen interactions. Microbiol. Mol. Biol. Rev. 82, 10–1128 (2018).
Wicha, S. G. et al. New in vitro interaction-parasite reduction ratio assay for early derisk in clinical development of antimalarial combinations. Antimicrob. Agents Chemother. 66, e00556-22 (2022).
Dembele, L. et al. The Plasmodium PI(4)K inhibitor KDU691 selectively inhibits dihydroartemisinin-pretreated Plasmodium falciparum ring-stage parasites. Sci. Rep. 7, 2325 (2017).
doi: 10.1038/s41598-017-02440-6
pubmed: 28539634
pmcid: 5443816
Chen, C., Wicha, S. G., Nordgren, R. & Simonsson, U. S. H. Comparisons of analysis methods for assessment of pharmacodynamic interactions including design recommendations. AAPS J. 20, 77 (2018).
doi: 10.1208/s12248-018-0239-0
pubmed: 29931471
Wicha, S. G., Kees, M. G., Kuss, J. & Kloft, C. Pharmacodynamic and response surface analysis of linezolid or vancomycin combined with meropenem against Staphylococcus aureus. Pharm. Res. 32, 2410–2418 (2015).
doi: 10.1007/s11095-015-1632-3
pubmed: 25630818
Wicha, S. G., Chen, C., Clewe, O. & Simonsson, U. S. H. A general pharmacodynamic interaction model identifies perpetrators and victims in drug interactions. Nat. Commun. 8, 2129 (2017).
doi: 10.1038/s41467-017-01929-y
pubmed: 29242552
pmcid: 5730559
Nielsen, E. I. & Friberg, L. E. Pharmacokinetic-pharmacodynamic modeling of antibacterial drugs. Pharmacol. Rev. 65, 1053–1090 (2013).
doi: 10.1124/pr.111.005769
pubmed: 23803529
Pearson, R. A., Wicha, S. G. & Okour, M. Drug combination modeling: methods and applications in drug development. J. Clin. Pharmacol. 63, 151–165 (2023).
doi: 10.1002/jcph.2128
pubmed: 36088583
Bergstrand, M., Hooker, A. C., Wallin, J. E. & Karlsson, M. O. Prediction-corrected visual predictive checks for diagnosing nonlinear mixed-effects models. AAPS J. 13, 143–151 (2011).
doi: 10.1208/s12248-011-9255-z
pubmed: 21302010
pmcid: 3085712
Stadler, E. et al. Propensity of selecting mutant parasites for the antimalarial drug cabamiquine. Nat. Commun. 14, 5205 (2023).
doi: 10.1038/s41467-023-40974-8
pubmed: 37626093
pmcid: 10457284
Courlet, P., Wilkins, J. J., Oeuvray, C., Gao, W. & Khandelwal, A. Semi-mechanistic population pharmacokinetic/pharmacodynamic modeling of a Plasmodium elongation factor 2 inhibitor cabamiquine for prevention and cure of malaria. Antimicrob. Agents Chemother. 67, e0089123 (2023).
doi: 10.1128/aac.00891-23
pubmed: 37966273
Wattanavijitkul, T. Population Pharmacokinetics of Pyronaridine in the Treatment of Malaria (University of Iowa, 2010).
Linares, M. et al. Identifying rapidly parasiticidal anti-malarial drugs using a simple and reliable in vitro parasite viability fast assay. Malar. J. 14, 441 (2015).
doi: 10.1186/s12936-015-0962-2
pubmed: 26542470
pmcid: 4635989
Sanz, L. M. et al. P. falciparum in vitro killing rates allow to discriminate between different antimalarial mode-of-action. PLoS ONE 7, e30949 (2012).
doi: 10.1371/journal.pone.0030949
pubmed: 22383983
pmcid: 3285618
Walz, A. et al. The parasite reduction ratio (PRR) assay version 2: standardized assessment of Plasmodium falciparum viability after antimalarial treatment in vitro. Pharmaceuticals 16, 163 (2023).
doi: 10.3390/ph16020163
pubmed: 37009844
pmcid: 9959027
Wockner, L. F. et al. Growth rate of Plasmodium falciparum: analysis of parasite growth data from malaria volunteer infection studies. J. Infect. Dis. 221, 963–972 (2020).
pubmed: 31679015
Gavigan, C. S., Machado, S. G., Dalton, J. P. & Bell, A. Analysis of antimalarial synergy between bestatin and endoprotease inhibitors using statistical response-surface modelling. Antimicrob. Agents Chemother. 45, 3175–3181 (2001).
doi: 10.1128/AAC.45.11.3175-3181.2001
pubmed: 11600374
pmcid: 90800
Roemhild, R. & Andersson, D. I. Mechanisms and therapeutic potential of collateral sensitivity to antibiotics. PLoS Pathog. 17, e1009172 (2021).
doi: 10.1371/journal.ppat.1009172
pubmed: 33444399
pmcid: 7808580
Walliker, D., Hunt, P. & Babiker, H. Fitness of drug-resistant malaria parasites. Acta Trop. 94, 251–259 (2005).
doi: 10.1016/j.actatropica.2005.04.005
pubmed: 15845348
Croft, S. L. et al. Review of pyronaridine anti-malarial properties and product characteristics. Malar. J. 11, 270 (2012).
doi: 10.1186/1475-2875-11-270
pubmed: 22877082
pmcid: 3483207
Dembele, L. et al. Ex vivo Plasmodium malariae culture method for antimalarial drugs screen in the field. ACS Infect. Dis. 7, 3025–3033 (2021).
doi: 10.1021/acsinfecdis.1c00262
pubmed: 34711047
pmcid: 9974065
Trager, W. & Jensen, J. B. Human malaria parasites in continuous culture. Science 193, 673–675 (1976).
Lambros, C. & Vanderberg, J. P. Synchronization of Plasmodium falciparum erythrocytic stages in culture. J. Parasitol. 65, 418 (1979).
doi: 10.2307/3280287
pubmed: 383936
Thiam, L. G., Ansah, F., Niang, M., Awandare, G. A. & Aniweh, Y. Short-term cryopreservation and thawing have minimal effects on Plasmodium falciparum ex vivo invasion profile. Front. Cell. Infect. Microbiol. 12, 997418 (2022).
doi: 10.3389/fcimb.2022.997418
pubmed: 36204649
pmcid: 9531135
Mohamed, A. F. et al. Dynamic interaction of colistin and meropenem on a WT and a resistant strain of Pseudomonas aeruginosa as quantified in a PK/PD model. J. Antimicrob. Chemother. 71, 1279–1290 (2016).
doi: 10.1093/jac/dkv488
pubmed: 26850719
Wicha, S. G., Huisinga, W. & Kloft, C. Translational pharmacometric evaluation of typical antibiotic broad-spectrum combination therapies against Staphylococcus aureus exploiting in vitro information. CPT Pharmacomet. Syst. Pharmacol. 6, 512–522 (2017).
doi: 10.1002/psp4.12197
Mouton, J. W. et al. The role of pharmacokinetics/pharmacodynamics in setting clinical MIC breakpoints: the EUCAST approach. Clin. Microbiol. Infect. 18, E37–E45 (2012).
doi: 10.1111/j.1469-0691.2011.03752.x
pubmed: 22264314