The effect of food consumption on lumefantrine bioavailability in African children receiving artemether-lumefantrine crushed or dispersible tablets (Coartem ® ) for acute uncomplicated Plasmodium falciparum malaria
2010; Wiley; Linguagem: Inglês
10.1111/j.1365-3156.2010.02477.x
ISSN1365-3156
AutoresSteffen Borrmann, William M. Sallas, Sónia Machevo, Raquel González, Anders Björkman, Andreas Mårtensson, Mary J. Hamel, Elizabeth Juma, Judy Peshu, Bernhards Ogutu, Abdoulaye Djimdé, Umberto D’Alessandro, A. C. Marrast, Gilbert Lefèvre, Steven E. Kern,
Tópico(s)Parasites and Host Interactions
ResumoTropical Medicine & International HealthVolume 15, Issue 4 p. 434-441 Free Access The effect of food consumption on lumefantrine bioavailability in African children receiving artemether–lumefantrine crushed or dispersible tablets (Coartem®) for acute uncomplicated Plasmodium falciparum malaria Steffen Borrmann, Steffen Borrmann Institute of Hygiene, University of Heidelberg School of Medicine, Heidelberg, Germany Kenya Medical Research Institute/Wellcome Trust Research Programme, Kilifi, KenyaSearch for more papers by this authorWilliam M. Sallas, William M. Sallas Department of Modeling and Simulation, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USASearch for more papers by this authorSonia Machevo, Sonia Machevo Manhiça Health Research Centre, Manhiça, MozambiqueSearch for more papers by this authorRaquel González, Raquel González Manhiça Health Research Centre, Manhiça, Mozambique Barcelona Centre for International Health Research, Hospital Clínic, Universitat de Barcelona, Barcelona, SpainSearch for more papers by this authorAnders Björkman, Anders Björkman Unit of Infectious Diseases, Karolinska University Hospital/Karolinska Institutet, Stockholm, SwedenSearch for more papers by this authorAndreas Mårtensson, Andreas Mårtensson Unit of Infectious Diseases, Karolinska University Hospital/Karolinska Institutet, Stockholm, Sweden Division of Global Health, Department of Public Health Sciences, Karolinska Institutet, Stockholm, SwedenSearch for more papers by this authorMary Hamel, Mary Hamel Kenya Medical Research Institute, Centre for Vector Biology and Control Research, Kisumu, KenyaSearch for more papers by this authorElizabeth Juma, Elizabeth Juma Kenya Medical Research Institute, Centre for Vector Biology and Control Research, Kisumu, KenyaSearch for more papers by this authorJudy Peshu, Judy Peshu Kenya Medical Research Institute/Wellcome Trust Research Programme, Kilifi, KenyaSearch for more papers by this authorBernhards Ogutu, Bernhards Ogutu Kenya Medical Research Institute/Walter Reed U.S. Army Institute, Kisumu, KenyaSearch for more papers by this authorAbdoulaye Djimdé, Abdoulaye Djimdé Molecular Epidemiology and Drug Resistance Unit, Malaria Research and Training Center, Faculty of Medicine, Pharmacy and Odonto-Stomatology, Bamako, MaliSearch for more papers by this authorUmberto D'Alessandro, Umberto D'Alessandro Institute of Tropical Medicine, Antwerp, BelgiumSearch for more papers by this authorAnne-Claire Marrast, Anne-Claire Marrast Global Program Tropical Medicine, Novartis Pharma AG, Basel, SwitzerlandSearch for more papers by this authorGilbert Lefèvre, Gilbert Lefèvre Translational Sciences, Novartis NIBR, Basel, SwitzerlandSearch for more papers by this authorSteven E. Kern, Steven E. Kern Department of Modeling and Simulation, Novartis Pharma AG, Basel, Switzerland Department of Pharmaceutics, University of Utah, Salt Lake City, UT, USASearch for more papers by this author Steffen Borrmann, Steffen Borrmann Institute of Hygiene, University of Heidelberg School of Medicine, Heidelberg, Germany Kenya Medical Research Institute/Wellcome Trust Research Programme, Kilifi, KenyaSearch for more papers by this authorWilliam M. Sallas, William M. Sallas Department of Modeling and Simulation, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USASearch for more papers by this authorSonia Machevo, Sonia Machevo Manhiça Health Research Centre, Manhiça, MozambiqueSearch for more papers by this authorRaquel González, Raquel González Manhiça Health Research Centre, Manhiça, Mozambique Barcelona Centre for International Health Research, Hospital Clínic, Universitat de Barcelona, Barcelona, SpainSearch for more papers by this authorAnders Björkman, Anders Björkman Unit of Infectious Diseases, Karolinska University Hospital/Karolinska Institutet, Stockholm, SwedenSearch for more papers by this authorAndreas Mårtensson, Andreas Mårtensson Unit of Infectious Diseases, Karolinska University Hospital/Karolinska Institutet, Stockholm, Sweden Division of Global Health, Department of Public Health Sciences, Karolinska Institutet, Stockholm, SwedenSearch for more papers by this authorMary Hamel, Mary Hamel Kenya Medical Research Institute, Centre for Vector Biology and Control Research, Kisumu, KenyaSearch for more papers by this authorElizabeth Juma, Elizabeth Juma Kenya Medical Research Institute, Centre for Vector Biology and Control Research, Kisumu, KenyaSearch for more papers by this authorJudy Peshu, Judy Peshu Kenya Medical Research Institute/Wellcome Trust Research Programme, Kilifi, KenyaSearch for more papers by this authorBernhards Ogutu, Bernhards Ogutu Kenya Medical Research Institute/Walter Reed U.S. Army Institute, Kisumu, KenyaSearch for more papers by this authorAbdoulaye Djimdé, Abdoulaye Djimdé Molecular Epidemiology and Drug Resistance Unit, Malaria Research and Training Center, Faculty of Medicine, Pharmacy and Odonto-Stomatology, Bamako, MaliSearch for more papers by this authorUmberto D'Alessandro, Umberto D'Alessandro Institute of Tropical Medicine, Antwerp, BelgiumSearch for more papers by this authorAnne-Claire Marrast, Anne-Claire Marrast Global Program Tropical Medicine, Novartis Pharma AG, Basel, SwitzerlandSearch for more papers by this authorGilbert Lefèvre, Gilbert Lefèvre Translational Sciences, Novartis NIBR, Basel, SwitzerlandSearch for more papers by this authorSteven E. Kern, Steven E. Kern Department of Modeling and Simulation, Novartis Pharma AG, Basel, Switzerland Department of Pharmaceutics, University of Utah, Salt Lake City, UT, USASearch for more papers by this author First published: 11 March 2010 https://doi.org/10.1111/j.1365-3156.2010.02477.xCitations: 18 Corresponding Author Steffen Borrmann, Institute of Hygiene, University of Heidelberg School of Medicine, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany. Tel.: 49 1577 7780721; E-mail: steffen.borrmann@urz.uni-heidelberg.de AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Summaryen Objectives Artemether–lumefantrine (AL) is first-line treatment for uncomplicated malaria in many African countries. Concomitant food consumption may affect absorption of lumefantrine but data in the most important target population, i.e. children, are lacking. Therefore, we evaluated the effect of food intake on oral lumefantrine bioavailability in African children with malaria. Methods In a randomised, investigator-blinded, multicentre phase III efficacy trial, 899 infants and children with acute uncomplicated Plasmodium falciparum malaria received six doses of AL according to body weight over 3 days either as crushed tablets (Coartem®) or as dispersible tablets. Single blood samples were obtained for lumefantrine plasma concentration determination in a subset of 621 patients, and a two-compartment pharmacokinetic model was constructed. Results The mean observed lumefantrine plasma concentration for crushed tablet and dispersible tablet, respectively, was 100% and 55% higher with a concomitant meal at the time of dose intake than when taken alone. Similarly, consumption of milk (the most common meal) increased model-estimated lumefantrine bioavailability by 57% (90% CI: 29–96%) with crushed tablets and 65% (90% CI: 28–109%) with dispersible tablets compared to no food. The 28-day PCR-corrected cure rate (primary study endpoint) in the evaluable population was 582/587 [99.1% (95% CI: 98.0–99.7%)] and was not related to food intake. Conclusions AL was highly efficacious. Concomitant food intake increased lumefantrine absorption in children with malaria. Abstractfr Effet de la nourriture sur la biodisponibilité du luméfantrine chez des enfants africains recevant des comprimés écrasés ou dispersibles d'artéméther-luméfantrine (Coartem®) contre la malaria aigüe non compliquée à Plasmodium falciparum Objectifs: l'artéméther-luméfantrine (AL) est un traitement de première intention contre la malaria sans complications dans de nombreux pays africains. La consommation concomitante d'aliments peu affecter l'absorption de la luméfantrine, mais des données sur la population cible la plus importante i.e. les enfants, font défaut. Par conséquent, nous avons évalué l'effet de la prise alimentaire sur la biodisponibilité orale de la luméfantrine chez des enfants africains atteints de malaria. Méthodes: Dans une étude d'efficacité randomisée, aveugle pour l'investigateur, multicentrique de phase III, 899 nourrissons et enfants atteints de malaria aigüe àPlasmodium falciparum non compliquée ont reçu six doses d'AL en fonction du poids du corps pendant 3 jours, soit en comprimés écrasés (Coartem®) ou sous forme de comprimés dispersibles. Des échantillons uniques de sang ont été prélevés pour la détermination de la concentration plasmatique de luméfantrine dans un sous-ensemble de 621 patients et un modèle pharmacocinétique bi compartimental a été construit. Résultats: Les concentrations plasmatiques moyennes de luméfantrine observées pour les comprimés écrasés et les comprimés dispersibles étaient de 100% et 55% respectivement plus élevée avec un repas concomitant au moment de la prise de la dose que lorsqu'ils étaient pris seuls. De même, la consommation de lait (le repas le plus commun) augmentait la biodisponibilité luméfantrine estimée par le model de 57% (IC90%: 29-96) avec les comprimés écrasés et 65% (IC90%: 28-109) avec les comprimés dispersibles, comparativement à l'absence de nourriture. Le taux de guérison au jour 28 corrigé par la PCR (critère d'évaluation primaire de l'étude) dans la population évaluable était de 582/587 (99,1% (IC95%: 98.0-99.7%)) et n'était pas liéà la prise alimentaire. Conclusions: AL était très efficace. La prise concomitante d'aliments augmente l'absorption de la luméfantrine chez les enfants atteints de malaria. Abstractes Efecto de la consumición de comida sobre la biodisponibilidad de la lumefantrina en niños Africanos que reciben comprimidos de artemeter-lumefantrina (Coartem®) triturados o dispersables para malaria aguda no complicada por Plasmodium falciparum Objetivos: La artemeter+lumefantrina (AL) es la primera línea de tratamiento para malaria no complicada en muchos países africanos. La consumición concomitante de comida puede afectar la absorción de la lumefantrina pero los datos en la población diana más importante, es decir, en niños, no existe. Por lo tanto, hemos evaluado el efecto de la toma de comidas sobre la biodisponibilidad de lumefantrina oral en niños africanos con malaria. Métodos: En un ensayo aleatorizado, cegado para el investigador, multicéntrico de fase 3, 899 bebés y niños con malaria aguda no complicada por Plasmodium falciparum recibieron seis dosis de AL según su peso corporal durante 3 días, bien como comprimidos triturados (Coartem®) o como comprimidos dispersables. Se obtuvieron dosis individuales de sangre para determinar la concentración de lumefantrina en sangre en un subgrupo de 621 pacientes y se construyó un modelo farmacocinético de dos compartimientos. Resultados: La concentración media observada de lumefantrina en sangre para los comprimidos triturados y los dispersables fué, respectivamente, de un 100% y un 55% más alto con una comida concomitante en el momento de tomar la dosis, que cuando se tomaba sola. De forma similar, la consumición de leche (la comida más común) aumentó la biodisponibilidad de lumefantrina según la estimación del modelo en un 57% (90% IC: 29% a 96%) con comprimidos triturados y del 65% (90% IC: 28% a 109%) con comprimidos dispersables comparado con el no haber tomado alimento alguno. La tasa de curación a día 28 corregida por PCR (resultado primario del estudio) en la población evaluada era 582/587 (99.1% (95% IC: 98.0-99.7%)) y no estaba relacionada con la toma de alimentos. Conclusiones: AL era altamente eficaz. La toma concomitante de comida aumentó la absorción de lumefantrina en niños con malaria. Introduction Despite intensive worldwide efforts to control malaria, almost a million deaths still occur each year, mostly in children aged <5 years (WHO World Malaria Report 2008). The logistical challenges in delivering prompt and effective treatment are compounded by the growing resistance of malaria parasites to conventional therapies. Multidrug resistant forms of Plasmodium falciparum, the parasite that causes the majority of malaria-related deaths, are now widespread in parts of Africa, the continent with the highest malaria burden (Roll Back Malaria 2008). As a response to this, new artemisinin-based combination therapies are now globally recommended as first-line treatments for uncomplicated P. falciparum malaria. The fixed-dose combination therapy containing artemether and lumefantrine (AL, Coartem®; Novartis Pharma AG, Basel, Switzerland) was pre-qualified by WHO in 2004 and has since then been deployed as first-line therapy in many endemic countries in Africa. AL is highly effective against acute, uncomplicated malaria caused by P. falciparum in areas of multidrug resistance (Van Vugt et al. 1999, 2000; Lefèvre et al. 2001; Piola et al. 2005; Falade et al. 2005; Mårtensson et al. 2005; Makanga et al. 2006). AL treatment is recommended to be taken together with food because of enhanced absorption of both artemether and lumefantrine in adult patients (White et al. 1999; Ezzet et al. 2000). However, the effect of food consumption on lumefantrine pharmacokinetics has never specifically been addressed in African children with malaria, the most important patient group, to whom results obtained in adults of different ethnic background may not necessarily apply. We report here an analysis of the impact of food consumption on lumefantrine pharmacokinetics and polymerase chain reaction (PCR)-corrected parasitological cure based on data obtained during a multicentre trial in children with acute uncomplicated P. falciparum malaria in five African countries (Abdulla et al. 2008). This trial included a pharmacokinetic evaluation of artemether [and its metabolite dihydroartemisinin (DHA)] and lumefantrine in patients receiving either the standard crushed tablet of AL or a dispersible formulation, the results of which have already been published (Abdulla et al. 2008). The objectives of the current analysis were to determine the relative impact on lumefantrine bioavailability of different foods eaten by patients concomitantly with drug administration in malarial-endemic regions of Africa, and to examine lumefantrine absorption in children who do not consume any food during AL administration. The rate of parasitological cure in subpopulations of patients who did or did not consume food at the time of AL dosing was also recorded. Methods Study design and conduct Pharmacokinetic data were obtained during a randomised, investigator-blinded, multicentre study conducted at eight centres in five countries with endemic malaria (Benin, Kenya, Mali, Mozambique and Tanzania). The study protocol has been described in detail previously (Abdulla et al. 2008). Briefly, infants and children with acute uncomplicated P. falciparum malaria were recruited following approval from an institutional review board located at each participating centre and from six European and US parent institutions of participating centres (Abdulla et al. 2008). Key inclusion criteria were age ≤12 years, body weight ≥5 kg and <35 kg, presence of fever (axillary or tympanic temperature ≥37.5 °C) or history of fever in the preceding 24 h, P. falciparum infection in blood ≥2000/μl and <200 000/μl, and absence of severe and complicated malaria according to the definition of WHO (WHO 2000). Exclusion criteria were haemoglobin <5 g/dl, antimalarial treatment other than chloroquine within the previous 2 weeks, prophylaxis with cotrimoxazole, use of any drug known to influence cardiac function in the preceding 4 weeks, corrected QT interval (QTc) prolongation or any condition known to prolong QTc and AL treatment within the past 30 days. Patients were randomly assigned to receive AL either as the commercially available tablet (Coartem®), crushed and mixed with a small quantity of water (10 ml), or as the new dispersible tablet formulation which was also administered with 10 ml of water. Each tablet contained 20 mg artemether and 120 mg lumefantrine. Patients received six doses at hours 0, 8, 24, 36, 48 and 60 (i.e. two doses each on study days 0, 1 and 2) according to body weight: one tablet per dose for patients weighing 5.0–14.9 kg, two tablets per dose for those weighing 15.0-24.9 kg and three tablets per dose for patients weighing 25.0–34.9 kg. Patients were hospitalised during the 3-day treatment phase. All doses of AL were administered under supervision, and intake of food/drink (including breast milk for breast-fed infants) at the time of dosing was encouraged by the investigators but with no specification as to the type or amount of food. Food consumption Food intake at the time of dosing was supervised and recorded by the clinical staff member who administered AL. Food was categorised as none, milk or breast feeding (including supplements), liquid (e.g. soup, broth), pancake (e.g. mandazi, fritter), porridge (e.g. groundnut, high energy protein supplement) or other (specified). All applicable items were checked. The quantity consumed was not recorded. Pharmacokinetic sample collection and bioanalytics Because this study was conducted in a very vulnerable population, pharmacokinetic samples were collected in two phases to minimise the burden to the patients. In the first 160 patients enrolled, plasma concentrations of artemether and its major active metabolite DHA were measured to support an interim futility analysis that could determine whether the occurrence of early treatment failures was related to insufficient artemether and/or DHA exposure. Following confirmation at the time of interim analysis that treatment outcome was adequate, the protocol specified that subsequently only lumefantrine plasma concentrations would be measured. In the latter group, a single blood sample was taken from each patient for the assessment of lumefantrine levels to avoid repeated blood samplings. This single sample was taken at one of six possible sampling times, as shown in Table 1. The most frequent time for a blood sample to be taken (50% of patients) was 6 h after the final sixth dose of AL, but sampling times continued to day 14, to take into account the long elimination half-life of lumefantrine. Table 1. Blood sampling scheme among patients providing samples for lumefantrine measurement. Each patient provided a single blood sample Sampling time* 6 h after dose 3 6 h after dose 5 6 h after dose 6 Day 3 (24 h after dose 6) Day 7 Day 14 Time after dose 1 (h) 30 54 66 84 168 336 N (dispersible) 29 30 158 26 31 32 N (crushed tablet) 32 31 163 23 32 30 % Patients 10 10 50 10 10 10 *Two additional patients in each treatment group provided blood samples at other timepoints which were included in the analysis. Blood samples were taken by venepuncture into heparinised tubes. Lumefantrine concentration in plasma was analysed by means of reversed-phase high-performance liquid chromatography method using liquid chromatography–tandem mass spectrometry (LC-MS/MS). The lower limit of quantification (LLOQ) for lumefantrine was 0.05 mg/l; values below this limit were set to 0 in all analyses. Over the calibration range of 0.0499–20 μg/ml, at the LLOQ, the coefficient of variability (% CV) for precision was 3.4% (n = 16) and the percentage bias for accuracy was −0.4% (n = 16). At other concentration levels, the % CV ranged from 2.8% to 4.9% and the bias percentage ranged from −4.5% to 5.4% (n = 16 per level). Over the quality control range of 0.100 μg/ml to 16 ug/ml, % CV ranged from 3.8% to 6.3% and the bias percentage ranged from −4.7% to 1.3% (n = 18 per level). Plasma analysis was performed centrally by Novartis Pharma S.A.S, Rueil-Malmaison, France. Population pharmacokinetic analysis The pharmacokinetic analysis was undertaken to estimate the relative bioavailability of lumefantrine according to both the type of meal consumed at the time of dosing (e.g. milk vs. no food) and the type of AL formulation (crushed vs. dispersible tablet). In particular, relative bioavailability was calculated. Relative bioavailability was defined as the ratio of bioavailability [i.e. the area under the concentration–time curve (AUC)] for a particular oral formulation when given with a particular type of meal to that of the reference formulation (crushed tablet) and the reference meal type (no food). A population pharmacokinetic analysis data set was constructed from actual date and time of dosing, and sampling events. Data on the blood concentration of lumefantrine from each of the single samples collected from patients receiving either crushed and dispersible tablets were first fitted separately and then pooled to characterise model-based relative differences in bioavailability attributable to the type of meal and formulation. In the model, clearances and volumes were allometrically scaled by body weight to the exponents 0.75 and 1.0, respectively (Anderson & Holford 2008). The effects of age on bioavailability were also explored. The likelihood function and diagnostic plots were used to assess goodness of fit and to refine model assumptions. PROC NLMIXED (SAS Release 8.2 on AIX 5.2 platform) was used to fit each model. Examination of standardised residuals from the final model vs. age, gender, baseline parasite count, treatment, weight, country, baseline body temperature indicated no reason to adjust the model according to these variables. Based on the final model, 90% confidence intervals (CIs) on the model-based relative bioavailability for comparing meal types and formulations were constructed by PROC NLMIXED and by the bootstrap method. The endpoints for the bootstrap CI were computed as the 5th and 95th percentiles of parameter estimates from 399 bootstrap samples where each bootstrap sample was stratified by treatment to include the same number of patients in the crushed treatment arm and dispersible treatment arm as used in the model. Confidence intervals for 28-day PCR-corrected cure rates were computed using the Clopper–Pearson method and F distribution (Newcombe 1998). Results Patient population In total, 899 patients were randomised during the study, of whom 452 (50.3%) received the crushed tablet. Blood samples for determination of lumefantrine concentration were obtained from 625/739 patients (84.6%) enrolled after the interim analysis. One patient assigned to the dispersible tablet group had no recorded date and time of sample collection. Three patients (one in the dispersible group and two in the crushed tablets group) whose samples were drawn on day 14 had lumefantrine concentrations that were more than 100-fold times the LLOQ when other patients had levels typically near or below the LLOQ, there was no known reason for this. As a result of these discrepancies, these four outliers were excluded from the pharmacokinetic analysis population, which thus comprised 621 patients (308 dispersible, 313 crushed tablet). In the pharmacokinetic analysis population, mean age was 4.1 ± 2.7 (median 3.4, range 0.25–12.4 years), 322 patients (51.9%) were men, and mean body weight was 14.4 ± 5.3 kg (median 13.1, range 5.0–34.0 kg). Patient demographics for this subpopulation were similar to the total study population and between groups receiving dispersible or crushed tablets (data not shown). The number of patients included in the pharmacokinetic analysis population from Benin, Kenya, Mali, Mozambique and Tanzania, respectively, was 105, 135, 86, 97 and 198. Mean parasite count (asexual forms) at enrolment was 48 000/μl (median 29 000/μl, range 500–629 000/μl). Mean body temperature was 38.1°C (median 38.0 °C, range 35.6–41.5 °C). Of the 621 patients included in the pharmacokinetic analysis, one patient received only two doses of AL and the remainder received the full six-dose treatment course. Thus, the total number of AL dosing events used in the model was 6 × 620 + 2 = 3722. Food intake Information on food intake was recorded for all 3722 doses. The predominant meal types were milk alone (57.4%), pancake alone (27.8%) and none (9.6%). These accounted for 94.8% of intake during the treatment phase. The distribution of meal types was similar between the two formulations (Table 2). Table 2. Food intake at or near the time of artemether–lumefantrine (AL) dosing. Information for all six AL doses are shown Dispersible tablet [n = 308 (1848 doses)] Crushed tablet [n = 313 (1874 doses)] Total [n = 621 (3722 doses)] No food 171 (9.3%) 187 (10.0%) 358 (9.6%) Milk alone 1066 (57.7%) 1069 (57.0%) 2135 (57.4%) Pancake alone 520 (28.1%) 516 (27.5%) 1036 (27.8%) Porridge alone 68 (3.7%) 74 (3.9%) 142 (3.8%) Soup alone 1 (0.1%) 4 (0.2%) 5 (0.1%) Other 21 (1.1%) 23 (1.2%) 44 (1.2%) Milk + other 1 (0.1%) 1 (0.1%) 2 (0.1%) Total doses administered 1848 (100.0%) 1874 (100.0%) 3722 (100.0%) Lumefantrine pharmacokinetics Overall, the mean observed lumefantrine concentration was 5.0 mg/l (n = 621). To assess the effect of food, the mean observed concentration was then calculated for only those patients who ate at the time of the last dose prior to collection of the pharmacokinetic blood sample. For the 550 patients who ate at the time of their last dose, the mean observed lumefantrine concentration was 5.3 mg/l. For the 71 patients who consumed no food at the time of their last dose prior to pharmacokinetic sampling collection, the mean observed lumefantrine concentration was 3.0 mg/l. With a concomitant meal at the time of the dose prior to pharmacokinetic sampling, mean observed lumefantrine plasma concentration was higher compared to no meal for both the dispersible and crushed tablet formulations (dispersible tablet, 4.8 mg/l (n = 277) with food vs. 3.1 mg/l (n = 31) without food, P = 0.003; crushed tablet, 5.8 mg/l (n = 273) with food vs. 2.9 mg/l (n = 40) without food, P < 0.001). When comparisons of food vs. no food at the time of each dose were broken down further by the sampling time and formulation, the sample sizes became small (n = 2 to n = 5) in the 'no food' category except for the 6-h sample after dose 6, where 50% of the samples were scheduled for collection. However, in spite of the small sample sizes, concentrations remained consistently higher in children with concomitant food intake compared to non-fed children in 11 of 12 cases (Figure 1). Figure 1Open in figure viewerPowerPoint Observed lumefantrine concentrations for patients receiving (a) dispersible (b) crushed tablet according to whether food was consumed at time of dose or not. Values shown are mean ± SE. The number of samples for the 'not fed' group was 3, 2, 17, 3, 3, and 3 for dispersible tablet and 2, 4, 21, 3, 5, and 5 for crushed tablet, respectively, at the following sampling points: 6 h after dose 3, 6 h after dose 5, 6 h after dose 6, day 3 (24 h after dose 6), day 7 and day 14. The number of samples for both formulations in the 'fed' group was approximately eight times as great as in the 'not fed' group and showed similar distribution across sampling times. The relative bioavailability of lumefantrine for the dispersible tablet compared to the crushed tablet was 0.93 (bootstrap 90% CI: 0.69–1.25) without consumption of food (Table 3). Concomitant food intake increased bioavailability of lumefantrine regardless of formulation (Figure 2). For a hypothetical 3.5- year-old child, consumption of milk or pancake increased bioavailability compared to no food by a factor ranging from 1.57 to 2.74 depending upon meal type and formulation. Specifically, consumption of milk increased lumefantrine bioavailability by 1.57 (bootstrap 90% CI: 1.29–1.96) vs. no food in children receiving the crushed tablet (Table 3). The relative bioavailability of lumefantrine for the dispersible tablet compared to the crushed tablet was 0.98 (bootstrap 90% CI: 0.84–1.11) with the consumption of milk. Table 3. Model-based relative lumefantrine bioavailability comparisons of meal type vs. not fed according to artemether–lumefantrine formulation Formulation Food intake Relative bioavailability Bootstrap90% CI Crushed tablet Milk vs. not fed 1.57 1.29, 1.96 Pancake vs. not fed 2.74 1.93, 3.61 Dispersible tablet Milk vs. not fed 1.65 1.28, 2.09 Pancake vs. not fed 1.83 1.42, 2.39 Figure 2Open in figure viewerPowerPoint Predicted plasma lumefantrine concentration vs. time after first dose by treatment and meal type for (a) dispersible (b) crushed tablets. When given a concomitant meal, regardless of formulation, older children had increased bioavailability compared to younger children (Figure 3). Among children who consumed food with their dose, a doubling of post-conceptional age (PCA) resulted in an increase in bioavailability of 20.281 = 1.22 (bootstrap 90% CI: 1.13–1.29). All children were assumed to have had a near full-term birth. Consequently, for example, an age of 0.75 years was transformed to a PCA of 1.5 years. The 22% increase pertained to any doubling of PCA across the age range of the study. Thus, for example, the estimate of
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