Population pharmacokinetics and pharmacodynamics of artemether and lumefantrine during combination treatment in children with uncomplicated falciparum malaria in Tanzania

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.

FIG. 1.

Artemether (solid lines) and dihydroartemisinin (dashed lines) concentrations over time during treatment with weight-based doses of artemether and lumefantrine (Coartem) administered at 0, 8, 24, 36, 48, and 60 h. Lines are interpolated between observations.

FIG. 2.

Observed lumefantrine concentrations over time during treatment with weight-based doses of artemether and lumefantrine (Coartem) administered at 0, 8, 24, 36, 48, and 60 h. Lines are interpolated between observations.

FIG. 3.

Observed parasitemia (solid lines) and body temperature (dashed lines) over time in pediatric patients during treatment with weight-based doses of artemether and lumefantrine administered at 0, 8, 24, 36, 48, and 60 h. Lines are interpolated between observations.

FIG. 4.

Trough concentrations of artemether and dihydroartemisinin (12 h postdose) during treatment with weight-based doses of artemether and lumefantrine (Coartem) administered at 0, 8, 24, 36, 48, and 60 h. The right panel shows the dihydroartemisinin/artemether ratio over time.

FIG. 5.

Visual predictive checks of the pharmacokinetic models. The open circles are the observed concentrations. The shaded area represents the 95% prediction interval, calculated from simulated observations from 1,000 studies.

FIG. 6.

Pharmacodynamic model based on the blood stages of P. falciparum. Compartments within the dashed rectangle represent parasites visible in peripheral blood.

FIG. 7.

Visual predictive check of the pharmacodynamic model. The open circles are the observed log-transformed parasitemias. The shaded area represents the 95% prediction interval, calculated from simulated observations from 1,000 studies, and the solid lines represent the simulated median parasitemia.