An artesunate pharmacometric model to explain therapeutic responses in falciparum malaria
Issued Date
2023-09-05
Resource Type
eISSN
14602091
Scopus ID
2-s2.0-85169847821
Pubmed ID
37473441
Journal Title
The Journal of antimicrobial chemotherapy
Volume
78
Issue
9
Start Page
2192
End Page
2202
Rights Holder(s)
SCOPUS
Bibliographic Citation
The Journal of antimicrobial chemotherapy Vol.78 No.9 (2023) , 2192-2202
Suggested Citation
Saralamba S., Simpson J.A., Choosri N., White L., Pan-Ngum W., Dondorp A.M., White N.J. An artesunate pharmacometric model to explain therapeutic responses in falciparum malaria. The Journal of antimicrobial chemotherapy Vol.78 No.9 (2023) , 2192-2202. 2202. doi:10.1093/jac/dkad219 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/90001
Title
An artesunate pharmacometric model to explain therapeutic responses in falciparum malaria
Other Contributor(s)
Abstract
BACKGROUND: The artemisinins are potent and widely used antimalarial drugs that are eliminated rapidly. A simple concentration-effect pharmacometric model does not explain why dosing more frequently than once daily fails to augment parasite clearance and improve therapeutic responses in vivo. Artemisinins can induce a temporary non-replicative or 'dormant' drug refractory state in Plasmodium falciparum malaria parasites which may explain recrudescences observed in clinical trials despite full drug susceptibility, but whether it explains the dosing-response relationship is uncertain. OBJECTIVES: To propose a revised model of antimalarial pharmacodynamics that incorporates reversible asexual parasite injury and temporary drug refractoriness in order to explain the failure of frequent dosing to augment therapeutic efficacy in falciparum malaria. METHODS: The model was fitted using a Bayesian Markov Chain Monte Carlo approach with the parasite clearance data from 39 patients with uncomplicated falciparum malaria treated with artesunate from western Cambodia and 40 patients from northwestern Thailand reported previously. RESULTS: The revised model captured the dynamics of parasite clearance data. Its predictions are consistent with observed therapeutic responses. CONCLUSIONS: A within-host pharmacometric model is proposed in which it is hypothesized that some malaria parasites enter a temporary drug refractory state after exposure to artemisinin antimalarials, which is followed by delayed parasite death or reactivation. The model fitted the observed sequential parasite density data from patients with acute P. falciparum malaria, and it supported reduced ring stage activity in artemisinin-resistant infections.