An artesunate pharmacometric model to explain therapeutic responses in falciparum malaria

Abstract Background The artemisinins are potent and widely used antimalarial drugs which 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 which incorporates reversible asexual parasite injury and temporary drug refractoriness in order to explain the failure of frequent dosing to augment therapeutic efficacy. Methods The model was fitted using 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 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 hypothesised 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.