Journal article

Development and Validation of an In Silico Decision Tool To Guide Optimization of Intravenous Artesunate Dosing Regimens for Severe Falciparum Malaria Patients

Sophie G Zaloumis, Jason M Whyte, Joel Tarning, Sanjeev Krishna, James M McCaw, Pengxing Cao, Michael T White, Saber Dini, Freya J Fowkes, Richard J Maude, Peter Kremsner, Arjen Dondorp, Ric N Price, Nicholas J White, Julie A Simpson



Most deaths from severe falciparum malaria occur within 24 h of presentation to a hospital. Intravenous (i.v.) artesunate is the first-line treatment for severe falciparum malaria, but its efficacy may be compromised by delayed parasitological responses. In patients with severe malaria, the life-saving benefit of the artemisinin derivatives is their ability to clear circulating parasites rapidly, before they can sequester and obstruct the microcirculation. To evaluate the dosing of i.v. artesunate for the treatment of artemisinin-sensitive and reduced ring stage sensitivity to artemisinin severe falciparum malaria infections, Bayesian pharmacokinetic-pharmacodynamic modeling of data from 94 ..

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Awarded by National Health and Medical Research Centre (NHMRC) of Australia

Awarded by Australian Centre for Research Excellence on Malaria Elimination - NHMRC

Awarded by Australian Research Council (ARC)

Awarded by NHMRC

Awarded by Australian Research Council

Funding Acknowledgements

We thank staff and patients at Chittagong Medical College Hospital in Bangladesh, Centre de Recherches Medicales de Lambarene and Universite des Sciences de la Sante in Gabon, and Queen Elizabeth Central Hospital in Malawi, where the data were collected. S.G.Z. and J.A.S. wrote the first draft of the manuscript; J.A.S. designed the research with input from R.N.P. and N.J.W.; P.K., S.K., A.D., N.J.W., and R.J.M. contributed the data; S.G.Z., J.M.W., and J.A.S. performed the statistical analysis with guidance from J.M.M, J.T., M.T.W., P.C., S.D., and F.J.I.F. All authors critically reviewed and approved the final version of the manuscript. We declare no competing interests for this work. The work was supported by the National Health and Medical Research Centre (NHMRC) of Australia project grant 1025319 and supported in part by the Australian Centre for Research Excellence on Malaria Elimination, funded by the NHMRC (1134989). S.G.Z. is funded by an Australian Research Council (ARC) Discovery Early Career Researcher Award (170100785), J.A.S. is supported by an NHMRC Senior Research Fellowship (1104975), F.J.I.F. is supported by an NHMRC Career Development Fellowship (1166753), R.N.P. is a Wellcome Trust senior research fellow in clinical science (200909), and N.J.W. is a Principal Wellcome Trust fellow. J.T., R.J.M., and A.D. are supported by the Wellcome Trust as part of the Wellcome Trust-Mahidol UniversityOxford Tropical Medicine Research Program. J.T. and R.J.M. are partly funded from the Bill & Melinda Gates Foundation. J.M.M., P.C., and J.A.S. are supported by an Australian Research Council Discovery Project (170103076).