Volume 11 Supplement 1

Challenges in malaria research

Open Access

An in silico drug treatment model to assess the robustness of regional age-based dosing regimens for artemisinin-based combination therapies

  • Eva Maria Staehli Hodel1,
  • Katherine Kay1,
  • Daniel Hayes1,
  • Anja Terlouw1 and
  • Ian Hastings1
Malaria Journal201211(Suppl 1):P91

https://doi.org/10.1186/1475-2875-11-S1-P91

Published: 15 October 2012

The standard drug development process for antimalarials and other drugs uses weight-based dosing (mg/kg) to predict blood concentrations of the drug, and hence their effect. Consequently, the current World Health Organization Guidelines for the treatment of malaria [1] provide target doses and therapeutic dose ranges in mg/ kg/day. However, in resource-poor settings, age-based dosing is often employed instead of weight-based dosing because of the scarcity of correctly functioning weighing scales outside of clinical settings. Due to the wide variation in weight by age this approach inevitably results in over- and under-dosing of a proportion of the population.

We have recently developed a modelling method to create statistically robust global and regional malaria-specific weight-for-age references representative of the malaria-endemic countries [2] and employed it to predict optimized age-based regimens for artemisinin-based combination therapies (ACTs) for case management of uncomplicated malaria (unpublished). The presented work now assesses the robustness of these age-based regimens using an in silico model of antimalarial drug treatment to predict treatment outcome based on individual infection parameters such as parasite numbers, variation in patient pharmacokinetics, and parasite variation in their drug sensitivity [3]. This extended pharmacokinetic/pharmakodynamic model for ACTs allowed us to investigate extreme treatment scenarios in a large number of patients over long follow-up periods that for ethical reasons could not be applied in clinical trials: typical examples include poor adherence (e.g. delayed, reduced or missed doses) or administration of doses above or below recommended therapeutic dose ranges and particularly in most vulnerable individuals such as infants and young children. Pharmacological modelling of antimalarial treatment cannot replace the gold standard of clinical trials, but the model outputs can identify patient groups that are at higher risk of treatment failure due to under-dosing or adverse events due to over-dosing.

We acknowledge the Medical Research Council for funding of this work.

Authors’ Affiliations

(1)
Liverpool School of Tropical Medicine

References

  1. World Health Organization: Guidelines for the treatment of malaria. 2010, Geneva, 2Google Scholar
  2. van Buuren S, Hayes DJ, Stasinopoulos DM, Rigby RA, ter Kuile FO, Terlouw DJ: Estimating regional centile curves from mixed data sources and countries. Statistics in Medicine. 2009, 28: 2891-2911. 10.1002/sim.3667.View ArticlePubMedGoogle Scholar
  3. Winter K, Hastings IM: Development, evaluation and application of an in silico model for antimalarial drug treatment and failure. Antimicrob Agents Chemother. 2011, 55: 3380-3392. 10.1128/AAC.01712-10.PubMed CentralView ArticlePubMedGoogle Scholar

Copyright

© Staehli Hodel et al; licensee BioMed Central Ltd. 2012

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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