Semi-mechanistic pharmacokinetic/pharmacodynamic modelling of the antimalarial effect of artemisinin
Language: 
English
Abstract: 

PURPOSE: To characterize artemisinin pharmacokinetics (PK) and its antimalarial activity in vivo. METHODS: Artemisinin salivary concentration and parasite count data were obtained from Vietnamese malaria patients receiving two different dosage regimens. PK data were analysed using a previously developed semiphysiological model incorporating autoinduction of eliminating enzymes. A pharmacodynamic (PD) model reflecting different stages of the parasite life-cycle was developed and fitted to the data. The model included visible and invisible compartments as well as sensitive, insensitive, and injured parasite stages. Salivary artemisinin concentrations functioned as the driving force for the observed decrease in the number of parasites. RESULTS: Large interindividual variability was observed in both PK and PD data. The PK model described reasonably well the observed decrease in salivary concentrations after repeated drug administration. The preinduction hepatic extraction ratio of artemisinin was estimated to be 0.87 with a volume of distribution of 27 L. Artemisinin half-life averaged 0.7 h. Incorporation of a saturable hepatic elimination affecting the first-pass extraction as well as a higher intrinsic clearance in female patients resulted in the best fit of the model to the data. The PD model described the decrease in the number of parasites during the course of treatment well. The longest mean transit time of parasites from sensitive, visible to invisible to insensitive visible stages was found to be 34.5 h through one life-cycle. The half-life of injured parasites was 2.7 h. CONCLUSIONS: The proposed semimechanistic PK/PD model successfully described the time course of both salivary artemisinin concentrations after repeated dosing and the number of parasites in patients treated with the drug.

Author(s): 
Gordi, Toufigh
Xie, Rujia
Jusko, William J.
Item Type: 
Journal Article
Publication Title: 
British Journal of Clinical Pharmacology
Journal Abbreviation: 
Br J Clin Pharmacol
Publication Date: 
12/5/2015
Publication Year: 
2005
Pages: 
594-604
Volume: 
60
Issue: 
6
ISSN: 
0306-5251
DOI: 
10.1111/j.1365-2125.2005.02508.x
Library Catalog: 
PubMed
Extra: 
PMID: 16305583 PMCID: PMC1884894

Turabian/Chicago Citation

Toufigh Gordi, Rujia Xie and William J. Jusko. 12/5/2015. "Semi-mechanistic pharmacokinetic/pharmacodynamic modelling of the antimalarial effect of artemisinin." British Journal of Clinical Pharmacology 60: 6: 594-604. 10.1111/j.1365-2125.2005.02508.x.

Wikipedia Citation

<ref> {{Cite journal | doi = 10.1111/j.1365-2125.2005.02508.x | issn = 0306-5251 | volume = 60 | pages = 594-604 | last = Gordi | first = Toufigh | coauthors = Xie, Rujia, Jusko, William J. | title = Semi-mechanistic pharmacokinetic/pharmacodynamic modelling of the antimalarial effect of artemisinin | journal = British Journal of Clinical Pharmacology | date = 12/5/2015 | pmid = | pmc = }} </ref>