Pharmacokinetics and Pharmacodynamics of Lumefantrine (Benflumetol) in Acute Falciparum Malaria

Abstract

The objective of this study was to conduct a prospective population pharmacokinetic and pharmacodynamic evaluation of lumefantrine during blinded comparisons of artemether-lumefantrine treatment regimens in uncomplicated multidrug-resistant falciparum malaria. Three combination regimens containing an average adult lumefantrine dose of 1,920 mg over 3 days (four doses) (regimen A) or 2,780 mg over 3 or 5 days (six doses) (regimen B or C, respectively) were given to 266 Thai patients. Detailed observations were obtained for 51 hospitalized adults, and sparse data were collected for 215 patients of all ages in a community setting. The population absorption half-life of lumefantrine was 4.5 h. The model-based median (5th and 95th percentiles) peak plasma lumefantrine concentrations were 6.2 (0.25 and 14.8) g/ml after regimen A, 9.0 (1.1 and 19.8) g/ml after regimen B, and 8 (1.4 and 17.4) g/ml after regimen C. During acute malaria, there was marked variability in the fraction of drug absorbed by patients (coefficient of variation, 150%). The fraction increased considerably and variability fell with clinical recovery, largely because food intake was resumed; taking a normal meal close to drug administration increased oral bioavailability by 108% (90% confidence interval, 64 to 164) (P, 0.0001). The higher-dose regimens (B and C) gave 60 and 100% higher areas under the concentration-time curves (AUC), respectively, and thus longer durations for which plasma lumefantrine concentrations exceeded the putative in vivo MIC of 280 g/ml (median for regimen B, 252 h; that for regimen C, 298 h; that for regimen A, 204 h [P, 0.0001]) and higher cure rates. Lumefantrine oral bioavailability is very dependent on food and is consequently poor in acute malaria but improves markedly with recovery. The high cure rates with the two six-dose regimens resulted from increased AUC and increased time at which lumefantrine concentrations were above the in vivo MIC.

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

“…24 Although a previous study in Thailand reported a Day 7 blood lumefantrine concentration cut-off point of 331 nmol/l (175 ng/ml), 25 another study in Malawi reported patients were cured even below this level. 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.…”

Artemether–Lumefantrine Concentrations in Tablets and Powders from Ghana Measured by a New High-Performance Liquid Chromatography Method

“…6 The World Health Organization's (WHO) recommendation of artemether-lumefantrine as first-line therapy for acute falciparum malaria in endemic areas 7 has led to widespread use of this fixed-dose combination in tablets, dispersible tablets (DTs), and powders meant for reconstitution into pediatric suspensions (PSs). Some studies have reported methods for the quantification of only artemether 8,9 or lumefantrine 10,11 in pharmaceutical and biological matrices. A few methods have been published for the simultaneous determination of artemether and lumefantrine in biological 3,12 and drug formulation matrices.…”

“…A few methods have been published for the simultaneous determination of artemether and lumefantrine in biological 3,12 and drug formulation matrices. 10,11 In 2011, Cesar and others 13 improved a method developed by Hodel and others 12 using liquid chromatography tandem mass spectrometry for the simultaneous quantification of artemether and lumefantrine of 14 antimalarials in human plasma, by eliminating a sample drying step and reducing the total chromatogram run time. Cesar and others in 2008 developed a method for the simultaneous quantification of artemether and lumefantrine in fixed-dose combination tablets using high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection.…”

Artemether‐Lumefantrine and Primaquine for Mixed Plasmodium falciparum and ovale Malaria

“…13 Lumefantrine oral bioavailability increases significantly if administered after a meal rich in fat and may be poor in acute malaria infection where nausea, vomiting and poor food intake are present. Pharmacists can educate and encourage patients to take their tablets with food or milk (if appetite is severely affected during acute infection).…”