title: Pharmacokinetic modelling of the anti-malarial drug artesunate and its active metabolite dihydroartemisinin.
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.
authors.affiliation: Departments of Mathematics and Statistics, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK. Electronic address: Adam.J.Hall@warwick.ac.uk.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Hall
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Chappell
authors.forename: John A D
authors.initials: JA
authors.lastname: Aston
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Ward
mesh_terms: D000328:Adult; D000962:Antimalarials / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D037621:Artemisinins / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000077332:Artesunate; D003198:Computer Simulation; D006801:Humans; D016778:Malaria, Falciparum / Q000097:blood / Q000188:drug therapy; D055641:Mathematical Concepts; D008954:Models, Biological
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D000077332:Artesunate; C039060:artenimol
keywords: Biomedical systems; Drug kinetics; Mathematical models; Parameter estimation; Sensitivity analysis; Structural identifiability