An artesunate pharmacometric model to explain therapeutic responses in falciparum malaria

Author:

Saralamba Sompob1ORCID,Simpson Julie A2,Choosri Noppon3,White Lisa4,Pan-Ngum Wirichada15ORCID,Dondorp Arjen M16,White Nicholas J16ORCID

Affiliation:

1. Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University , Bangkok , Thailand

2. Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne , Melbourne, Victoria , Australia

3. Center of Data Analytics and Knowledge Synthesis for Healthcare, Chiang Mai University , Chiang Mai , Thailand

4. Department of Biology, University of Oxford , Oxford , UK

5. Department of Tropical Hygiene, Faculty of Tropical Medicine, Mahidol University , Bangkok , Thailand

6. Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford , Oxford , UK

Abstract

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.

Publisher

Oxford University Press (OUP)

Subject

Infectious Diseases,Pharmacology (medical),Pharmacology,Microbiology (medical)

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