Population Pharmacokinetics of Artemether, Lumefantrine, and Their Respective Metabolites in Papua New Guinean Children with Uncomplicated Malaria

Abstract

There are sparse published data relating to the pharmacokinetic properties of artemether, lumefantrine, and their active metabolites in children, especially desbutyl-lumefantrine. We studied 13 Papua New Guinean children aged 5 to 10 years with uncomplicated malaria who received the six recommended doses of artemether (1.7 mg/kg of body weight) plus lumefantrine (10 mg/kg), given with fat over 3 days. Intensive blood sampling was carried out over 42 days. Plasma artemether, dihydroartemisinin, lumefantrine, and desbutyl-lumefantrine were assayed using liquid chromatography-mass spectrometry or high-performance liquid chromatography. Multicompartmental pharmacokinetic models for a drug plus its metabolite were developed using a population approach that included plasma artemether and dihydroartemisinin concentrations below the limit of quantitation. Although artemether bioavailability was variable and its clearance increased by 67.8% with each dose, the median areas under the plasma concentration-time curve from 0 h to infinity (AUC 0-ؕ s) for artemether and dihydroartemisinin (3,063 and 2,839 g ⅐ h/liter, respectively) were similar to those reported previously in adults with malaria. For lumefantrine, the median AUC 0-ؕ (459,980 g ⅐ h/liter) was also similar to that in adults with malaria. These data support the higher dose recommended for children weighing 15 to 35 kg (35% higher than that for a 50-kg adult) but question the recommendation for a lower dose in children weighing 12.5 to 15 kg. The median desbutyl-lumefantrine/lumefantrine ratio in the children in our study was 1.13%, within the range reported for adults and higher at later time points because of the longer desbutyllumefantrine terminal elimination half-life. A combined desbutyl-lumefantrine and lumefantrine AUC 0-ؕ weighted on in vitro antimalarial activity was inversely associated with recurrent parasitemia, suggesting that both the parent drug and the metabolite contribute to the treatment outcome of artemether-lumefantrine.

HIV-Positive Nigerian Adults Harbor Significantly Higher Serum Lumefantrine Levels than HIV-Negative Individuals Seven Days after Treatment for Plasmodium falciparum Infection

“…However, NVP stimulation of the CYP3A4 isoenzyme would be expected, a priori, to lower peripheral lumefantrine levels, due to an increase in the amount of lumefantrine metabolized to desbutyl-lumefantrine, a potent derivative that is normally found at a concentration between 0.5% and 5% of that of the parent compound at day 7 in the few studies available (8,20). Food intake also alters lumefantrine metabolism; we were not a All 167 individuals were reported as positive for P. falciparum parasites on microscopic examination of thick blood films.…”

“…Artemether is metabolized in the liver by the isoenzyme CYP3A4, to its active metabolite dihydroartemisinin (DHA), with peak plasma concentration being reached around 2 to 3 h after oral administration (4); elimination half-life is estimated at approximately 1 h. There is thus only limited opportunity for DHA to participate in drug-drug interactions. Lumefantrine is partially metabolized to desbutyl-lumefantrine, predominantly through CYP3A4, reaching peak plasma levels approximately 10 h after oral administration, and is then cleared slowly, showing a terminal half-life of 4 to 6 days in P. falciparum malaria cases (5)(6)(7)(8)(9). Oral bioavailability of lumefantrine is variable and highly dependent on administration with fatty foods (5,9,10).…”

Population Pharmacokinetics, Tolerability, and Safety of Dihydroartemisinin-Piperaquine and Sulfadoxine-Pyrimethamine-Piperaquine in Pregnant and Nonpregnant Papua New Guinean Women

“…Once the structures of the models were established, interindividual variability (IIV), interoccasion variability (IOV), and correlations between IIV terms were estimated, where supported by the data. In particular, IOV of F PQ (relative bioavailability) was estimated to examine the potential differences in the relative bioavailability of PQ between doses, as noted previously for PQ and other lipophilic antimalarial drugs (31,35,39).…”

“…Plasma DHA concentrations were measured by liquid chromatography-mass spectrometry as previously described using solid-phase extraction and reversed-phase chromatography (35). In brief, extracted plasma samples were injected onto a Synergy fusion-RP C 18 (150-by 2.0-mm internal diameter) column coupled with a 4-mm by 3-mm internal diameter 5-m C 18 guard column (Phenomenex).…”

Pharmacokinetics of a Novel Sublingual Spray Formulation of the Antimalarial Drug Artemether in African Children with Malaria

“…Artemether-lumefantrine is a safe and effective treatment for uncomplicated pediatric malaria (3,4), but there is evidence of significant between-dose variability in absorption even when coadministered with a small amount of fat to improve bioavailability (5). In addition, the nausea and vomiting that are frequently associated with malaria, together with an unwell child's refusal to feed or take medications by mouth (6), can reduce the effectiveness of oral treatment through reduced adherence to the World Health Organization (WHO) recommended 3-day regimen (7).…”