Abstract
Objective: To examine the kinetics of the disposition of Plasmodium falciparum during treatment with antimalarial drugs in 565 children presenting with acute, symptomatic, uncomplicated malaria.Methods: We conducted a prospective study using conventional principles for the disposition of drugs to characterise the kinetics of the disposition of parasitaemia in children treated with antimalarial drugs. We also evaluated the relationship between the indices of parasite kinetics and the conventional indices of therapeutic response to antimalarial drugs. Parasite kinetic parameters were estimated from parasite densities (parasite concentrations) by the noncompartmental method.Results: In drug-sensitive P. falciparum infections, the areas under the parasite density versus time curve (AUC) increased in proportion to parasite load from 2500 to 320 000 asexual forms/µl blood [p = 0.0004, analysis of variance (ANOVA)], but there was no significant difference in the half-lives of reduction of parasitaemia (t), the volume of blood completely cleared of parasites per unit time (CL) or the parasite density : AUC ratio, indicating that the kinetics of the disposition of parasitaemia were linear in the concentration range examined. In drug-sensitive infections, AUC, t and CL were similar for chloroquine, pyrimethamine-sulfadoxine, halofantrine, chloroquine plus chlorphenamine (chlorpheniramine), and cotrimoxazole (trimethoprim-sulfamethoxazole). However, t was significantly lower (p = 0.00001, ANOVA) and CLsignificantly higher (p = 0.00001, ANOVA) for artemether when compared with other antimalarials used in sensitive infections, suggesting a relatively superior rapidity of action. In age, gender and parasite-density matched children, CL was significantly higher (p = 0.00003) in sensitive than in moderately or severely resistant infections. In treatment-sensitive infections, there was a correlation between tand parasite clearance time (PCT) [r = 0.988, p = 0.00001]. The PCT : t ratio was similar for all drugs (range 18-21; p = 0.072, ANOVA) and remained constant (p = 0.925, ANOVA) irrespective of PCT. A new index to classify the rapidity of action of antimalarial drugs in vivo based on the relationship between t and PCT is presented.Conclusions: The kinetics of the disposition of P. falciparum parasitaemia in children with drug-sensitive infections are linear. The kinetic and other derived indices presented here may be used to evaluate and monitor the therapeutic responses of infections and the rapidity of antimalarial action in children.
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