The combination of
artemether (ARM) and
lumefantrine is currently the first-line treatment of uncomplicated
falciparum malaria in mainland Tanzania. While the exposure to
lumefantrine has been associated with the probability of adequate clinical and parasitological cure, increasing exposure to
artemether and the active metabolite
dihydroartemisinin (DHA) has been shown to decrease the parasite clearance time. The aim of this analysis was to describe the pharmacokinetics and pharmacodynamics of
artemether,
dihydroartemisinin, and
lumefantrine in African children with uncomplicated
malaria. In addition to
drug concentrations and
parasitemias from 50 Tanzanian children with
falciparum malaria, peripheral parasite densities from 11 asymptomatic children were included in the model of the parasite dynamics. The population pharmacokinetics and pharmacodynamics of
artemether,
dihydroartemisinin, and
lumefantrine were modeled in NONMEM. The distribution of
artemether was described by a two-compartment model with a rapid absorption and elimination through metabolism to
dihydroartemisinin.
Dihydroartemisinin concentrations were adequately illustrated by a one-compartment model. The pharmacokinetics of
artemether was time dependent, with typical oral clearance increasing from 2.6 liters/h/kg on day 1 to 10 liters/h/kg on day 3. The pharmacokinetics of
lumefantrine was sufficiently described by a one-compartment model with an absorption lag time. The typical value of oral clearance was estimated to 77 ml/h/kg. The proposed semimechanistic model of parasite dynamics, while a rough approximation of the complex interplay between
malaria parasite and the human host, adequately described the early effect of ARM and DHA concentrations on the parasite density in
malaria patients. However, the poor precision in some parameters illustrates the need for further data to support and refine this model.