Publication: Development and validation of an in silico decision tool to guide optimization of intravenous artesunate dosing regimens for severe falciparum malaria patients
Issued Date
2021-06-01
Resource Type
ISSN
10986596
00664804
00664804
Other identifier(s)
2-s2.0-85106222020
Rights
Mahidol University
Rights Holder(s)
SCOPUS
Bibliographic Citation
Antimicrobial Agents and Chemotherapy. Vol.65, No.6 (2021)
Suggested Citation
Sophie G. Zaloumis, Jason M. Whyte, Joel Tarning, Sanjeev Krishna, James M. McCaw, Pengxing Cao, Michael T. White, Saber Dini, Freya J.I. Fowkes, Richard J. Maude, Peter Kremsner, Arjen Dondorp, Ric N. Price, Nicholas J. White, Julie A. Simpson Development and validation of an in silico decision tool to guide optimization of intravenous artesunate dosing regimens for severe falciparum malaria patients. Antimicrobial Agents and Chemotherapy. Vol.65, No.6 (2021). doi:10.1128/AAC.02346-20 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/78166
Research Projects
Organizational Units
Authors
Journal Issue
Thesis
Title
Development and validation of an in silico decision tool to guide optimization of intravenous artesunate dosing regimens for severe falciparum malaria patients
Other Contributor(s)
Faculty of Tropical Medicine, Mahidol University
Melbourne School of Population and Global Health
University of London
Harvard T.H. Chan School of Public Health
University of Melbourne
Menzies School of Health Research
Eberhard Karls Universität Tübingen
Nuffield Department of Medicine
Burnet Institute
Institut Pasteur, Paris
Centre de Recherches Médicales de Lambaréné
Melbourne School of Population and Global Health
University of London
Harvard T.H. Chan School of Public Health
University of Melbourne
Menzies School of Health Research
Eberhard Karls Universität Tübingen
Nuffield Department of Medicine
Burnet Institute
Institut Pasteur, Paris
Centre de Recherches Médicales de Lambaréné
Abstract
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 patients with severe malaria (80 children from Africa and 14 adults from Southeast Asia) was performed. Assuming that delayed parasite clearance reflects a loss of ring stage sensitivity to artemisinin derivatives, the median (95% credible interval) percentage of patients clearing $99% of parasites within 24 h (PC24$99%) for standard (2.4 mg/kg body weight i.v. artesunate at 0 and 12 h) and simplified (4 mg/kg i.v. artesunate at 0 h) regimens was 65% (52.5% to 74.5%) versus 44% (25% to 61.5%) for adults, 62% (51.5% to 74.5%) versus 39% (20.5% to 58.5%) for larger children ($20 kg), and 60% (48.5% to 70%) versus 36% (20% to 53.5%) for smaller children (,20 kg). The upper limit of the credible intervals for all regimens was below a PC24$99% of 80%, a threshold achieved on average in clinical studies of severe falciparum malaria infections. In severe falciparum malaria caused by parasites with reduced ring stage susceptibility to artemisinin, parasite clearance is predicted to be slower with both the currently recommended and proposed simplified i.v. artesunate dosing regimens.