How much fat is necessary to optimize lumefantrine oral bioavailability?

Abstract

Summarybackground Artemether-lumefantrine (AL) is the only fixed, artemisinin-based combination antimalarial drug which is registered internationally and deployed on a large scale. Absorption of the hydrophobic lipophilic lumefantrine component varies widely between individuals and is greatly increased by fat coadministration; but patients with acute malaria are frequently nauseated and anorexic, making dietary advice difficult to comply with. The aim of this study was to describe the doseresponse relationship between coadministration of fat and relative lumefantrine bioavailability, in order to determine the minimum amount of fat necessary to optimize absorption.method We conducted a multiple crossover pharmacokinetic study in 12 healthy volunteers. This compared the area under the plasma concentration-time curve (AUC) for lumefantrine after administration of a single dose of AL in the fasting state given with 0, 10, 40, 150 and 500 ml of soya milk corresponding to 0, 0.32, 1.28, 4.8 and 16 g of fat. All volumes of milk supplements were tested in all subjects with a 3-to 4-week washout period in-between.results A dose-response relationship was demonstrated between the volume of soya milk administered and lumefantrine bioavailability. AL administration with soya milk increased the lumefantrine AUC more than five fold. The population mean estimated volume of soya milk required to obtain 90% of maximum effect (in terms of lumefantrine AUC) was 36 ml (corresponding to 1.2 g of fat).conclusions Coadministration of artemether-lumefantrine with a relatively small amount of fat (as soya milk) was required to ensure maximum absorption of lumefantrine in healthy adult volunteers.

Adherence to artemether/lumefantrine treatment in children under real-life situations in rural Tanzania

“…24 The difference might be explained by possible variations in food intake, 26 as the levels of lumefantrine blood concentrations may increase 16-fold in patients who took the drug with fatty food compared with without fat. 27,28 Age-based dosage schedules of ALu might also explain the unpredictable blood concentrations of lumefantrine, since the dose per kg may vary widely between patients, as reported for the CQ/SP combination. 29 This underscores the need to monitor the rate of adherence to treatment guidelines by providers as well as treatment schedules among patients in rural areas when implementing ALu treatment on a wide scale in Africa.…”

Pharmacokinetic Comparison of Two Piperaquine-Containing Artemisinin Combination Therapies in Papua New Guinean Children with Uncomplicated Malaria

“…The full contents of each sachet were mixed with at least 50 ml of cow's milk (equivalent to 2 g of fat), as fat has been reported to increase the bioavailability of PQ tetraphosphate (25,41). The volume of milk used was based on previous experience with its palatability and association with nausea in PNG children as well as on the amount of fat found to maximize the absorption of lumefantrine, another highly lipophilic antimalarial drug, in healthy adults (5).…”

“…Chromatographic data (peak area ratio of ART/ARM) were processed using the LAB Solution software package (version 5; Shimadzu, Japan). Responses from analysis of samples containing three different ART concentrations (5,200, and 2,000 g/ liter) and one ARM concentration (1,000 g/liter) spiked into five separate plasma samples were used to determine matrix effects (ion suppression/enhancement), absolute recovery, and process efficiency (32), which were between 90% and 98%, 82% and 93%, and 86% and 91%, respectively. The assay intraday RSDs were 9.3, 7.2, and 3.7% and interday RSDs were 9.5, 7.1, and 6.5% at 5, 200, and 2,000 g/liter, respectively.…”

Antimalarial Drugs – What is in Use and What is in the Pipeline

“…Oral absorption of this highly lipophilic drug is 16-fold enhanced when taken with a fatty meal. It has been shown that 1.3 g of fat (best taken as milk) is sufficient to improve lumefantrine bioavailability [55]. In contrast to halofantrine 5, lumefantrine 6 is not associated with dangerous cardiac side effect [56].…”