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. I. Fowkes, Richard J. Maude, Peter Kremsner, Arjen Dondorp, Ric N. Price, Nicholas J. White, Julie A. Simpson

Research output: Contribution to journalArticleAcademicpeer-review

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.
Original languageEnglish
Article numbere02346
JournalAntimicrobial Agents and Chemotherapy
Volume65
Issue number6
DOIs
Publication statusPublished - 1 Jun 2021

Keywords

  • Intravenous artesunate
  • Pharmacokinetic-pharmacodynamic modeling
  • Plasmodium falciparum
  • Severe malaria

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