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

• Published in: Computer methods and programs in biomedicine Vol. 112; no. 1; pp. 1 - 15
• Main Authors: Hall, Adam J, Chappell, Michael J, Aston, John A.D, Ward, Stephen A
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Ireland Ltd 01.10.2013; Elsevier
• Subjects: Adult; Antimalarials - administration & dosage; Antimalarials - blood; Antimalarials - pharmacokinetics; Artemisinins - administration & dosage; Artemisinins - blood; Artemisinins - pharmacokinetics; Biological and medical sciences; Biomedical systems; Compartments; Computer programs; Computer Simulation; Drug kinetics; Drugs; General pharmacology; Humans; Internal Medicine; Malaria, Falciparum - blood; Malaria, Falciparum - drug therapy; Mathematical Concepts; Mathematical models; Medical sciences; Metabolites; Modelling; Models, Biological; Other; Parameter estimation; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions; Pharmacology. Drug treatments; Sensitivity analysis; Structural identifiability; Parameter estimation; Mathematical models; Drug kinetics; Structural identifiability; Sensitivity analysis; Biomedical systems; Drug; Validation; Protozoal disease; Identifiability; Malaria; Metabolite; Variability; Oral administration; Parasitosis; Modeling; Optimization; Infection; Structural model; System identification; Pharmacokinetics; Concentration distribution; Biomedical engineering
• ISSN: 0169-2607; 1872-7565
• DOI: 10.1016/j.cmpb.2013.05.010

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.