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An artesunate pharmacometric model to explain therapeutic responses in falciparum malaria

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. Artemi...

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Autores principales: Saralamba, Sompob, Simpson, Julie A, Choosri, Noppon, White, Lisa, Pan-Ngum, Wirichada, Dondorp, Arjen M, White, Nicholas J
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10477127/
https://www.ncbi.nlm.nih.gov/pubmed/37473441
http://dx.doi.org/10.1093/jac/dkad219
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author Saralamba, Sompob
Simpson, Julie A
Choosri, Noppon
White, Lisa
Pan-Ngum, Wirichada
Dondorp, Arjen M
White, Nicholas J
author_facet Saralamba, Sompob
Simpson, Julie A
Choosri, Noppon
White, Lisa
Pan-Ngum, Wirichada
Dondorp, Arjen M
White, Nicholas J
author_sort Saralamba, Sompob
collection PubMed
description 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.
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spelling pubmed-104771272023-09-06 An artesunate pharmacometric model to explain therapeutic responses in falciparum malaria Saralamba, Sompob Simpson, Julie A Choosri, Noppon White, Lisa Pan-Ngum, Wirichada Dondorp, Arjen M White, Nicholas J J Antimicrob Chemother Original Research 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. Oxford University Press 2023-07-20 /pmc/articles/PMC10477127/ /pubmed/37473441 http://dx.doi.org/10.1093/jac/dkad219 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Research
Saralamba, Sompob
Simpson, Julie A
Choosri, Noppon
White, Lisa
Pan-Ngum, Wirichada
Dondorp, Arjen M
White, Nicholas J
An artesunate pharmacometric model to explain therapeutic responses in falciparum malaria
title An artesunate pharmacometric model to explain therapeutic responses in falciparum malaria
title_full An artesunate pharmacometric model to explain therapeutic responses in falciparum malaria
title_fullStr An artesunate pharmacometric model to explain therapeutic responses in falciparum malaria
title_full_unstemmed An artesunate pharmacometric model to explain therapeutic responses in falciparum malaria
title_short An artesunate pharmacometric model to explain therapeutic responses in falciparum malaria
title_sort artesunate pharmacometric model to explain therapeutic responses in falciparum malaria
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10477127/
https://www.ncbi.nlm.nih.gov/pubmed/37473441
http://dx.doi.org/10.1093/jac/dkad219
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