Reprint of "Pharmacokinetic modelling of the anti-malarial drug artesunate and its active metabolite dihydroartemisinin"

Adam J Hall; Michael J Chappell; John A D Aston; Stephen A Ward

doi:10.1016/j.cmpb.2013.12.001

Reprint of "Pharmacokinetic modelling of the anti-malarial drug artesunate and its active metabolite dihydroartemisinin"

Comput Methods Programs Biomed. 2014 May;114(3):e14-28. doi: 10.1016/j.cmpb.2013.12.001. Epub 2014 Jan 20.

Authors

Adam J Hall¹, Michael J Chappell², John A D Aston³, Stephen A Ward⁴

Affiliations

¹ Departments of Mathematics and Statistics, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK. Electronic address: Adam.J.Hall@warwick.ac.uk.
² School of Engineering, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK.
³ Department of Statistics, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK.
⁴ Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK.

PMID: 24457047
DOI: 10.1016/j.cmpb.2013.12.001

Abstract

A four compartment mechanistic mathematical model is developed for the pharmacokinetics of the commonly used anti-malarial drug artesunate and its principle metabolite dihydroartemisinin following oral administration of artesunate. The model is structurally unidentifiable unless additional constraints are imposed. Combinations of mechanistically derived constraints are considered to assess their effects on structural identifiability and on model fits. Certain combinations of the constraints give rise to locally or globally identifiable model structures. Initial validation of the model under various combinations of the constraints leading to identifiable model structures was performed against a dataset of artesunate and dihydroartemisinin concentration-time profiles of 19 malaria patients. When all the discussed constraints were imposed on the model, the resulting globally identifiable model structure was found to fit reasonably well to those patients with normal drug absorption profiles. However, there is wide variability in the fitted parameters and further investigation is warranted.

Keywords: Biomedical systems; Drug kinetics; Mathematical models; Parameter estimation; Sensitivity analysis; Structural identifiability.