Abstract:
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.
