Development and validation of an 'in silico' decision-tool to guide optimisation of intravenous artesunate dosing regimens for severe falciparum malaria patients

Zaloumis, SG; Whyte, JM; Tarning, J; Krishna, S; McCaw, JM; Cao, P; White, MT; Dini, S; Fowkes, FJI; Maude, RJ; Kremsner, P; Dondorp, A; Price, RN; White, NJ; Simpson, JA

Journal article

Development and validation of an 'in silico' decision-tool to guide optimisation of intravenous artesunate dosing regimens for severe falciparum malaria patients

Abstract:: Most deaths from severe falciparum malaria occur within 24 hours of presentation to 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 modelling of data from 94 patients with severe malaria (80 children from Africa and 14 adults from Southeast Asia) was performed. Assuming delayed parasite clearance reflects a loss of ring stage sensitivity to artemisinin derivatives, the median (95% credible interval) percentage of patients clearing ≥99% parasites within 24 hours (PC24≥99%) for standard (2.4 mg/kg i.v. artesunate at 0 and 12 hours) and simplified (4 mg/kg i.v. artesunate at 0 hours) regimens were 65% (52.5%-74.5%) versus 44% (25%-61.5%) for adults, 62% (51.5%-74.5%) versus 39% (20.5%-58.5%) for larger children (≥20 kg) and 60% (48.5%-70%) versus 36% (20%-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. Rapid clearance of parasites, where there is loss of ring stage sensitivity to artemisinin, in patients with severe falciparum malaria is compromised with the currently recommended and proposed simplified i.v. artesunate dosing regimens.

Publication status:: Published

Peer review status:: Peer reviewed

Actions

Email

Email this record

Send the bibliographic details of this record to your email address.

Your Email
Please enter the email address that the record information will be sent to.

-
Your message (optional)
Please add any additional information to be included within the email.
Share
Cite

Cite this record

APA Style

Zaloumis, S. G., Whyte, J. M., Tarning, J., Krishna, S., McCaw, J. M., Cao, P., White, M. T., Dini, S., Fowkes, F. J. I., Maude, R. J., Kremsner, P., Dondorp, A., Price, R. N., White, N. J., & Simpson, J. A. (2021). Development and validation of an 'in silico' decision-tool to guide optimisation of intravenous artesunate dosing regimens for severe falciparum malaria patients. Antimicrobial Agents and Chemotherapy, 65(6).

MLA Style

Zaloumis, SG, et al. “Development and Validation of an 'in Silico' Decision-Tool to Guide Optimisation of Intravenous Artesunate Dosing Regimens for Severe Falciparum Malaria Patients.” Antimicrobial Agents and Chemotherapy, vol. 65, no. 6, 2021.

Chicago Style

Zaloumis, SG, JM Whyte, J Tarning, et al. 2021. “Development and Validation of an 'in Silico' Decision-Tool to Guide Optimisation of Intravenous Artesunate Dosing Regimens for Severe Falciparum Malaria Patients.” Antimicrobial Agents and Chemotherapy 65 (6).
Print