A field-adapted sampling and HPLC quantification method for lumefantrine and its desbutyl metabolite in whole blood spotted on filter paper

Ntale, Muhammad; Ogwal-Okeng, Jasper; Mahindi, Margarita; Gustafsson, Lars L.; Beck, Olof

doi:10.1016/j.jchromb.2008.11.002

Cited by 23 publications

(37 citation statements)

References 24 publications

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“…RAs collected capillary blood samples from the children on Day 7 through a finger-prick using the method previously described by Ntale et al 20 After drying the filter paper, the specimen was stored in a plastic envelope to avoid contamination and was collected by the supervisors weekly. Filter paper samples were stored at room temperature for 3-15 months at the Pharmacology Laboratory of Muhimbili University (Dar es Salaam, Tanzania) before transfer to the Clinical Pharmacology Laboratory at Karolinska Institutet (Stockholm, Sweden) where blood lumefantrine concentrations were determined by HPLC as described by Ntale et al 20 Samples were assayed with an intra-assay and inter-assay coefficient of variation of <9.2% and with a limit of quantification (LoQ) of 25 nmol/l.…”

Section: Blood Sampling Handling and Drug Sample Analysismentioning

confidence: 99%

“…Filter paper samples were stored at room temperature for 3-15 months at the Pharmacology Laboratory of Muhimbili University (Dar es Salaam, Tanzania) before transfer to the Clinical Pharmacology Laboratory at Karolinska Institutet (Stockholm, Sweden) where blood lumefantrine concentrations were determined by HPLC as described by Ntale et al 20 Samples were assayed with an intra-assay and inter-assay coefficient of variation of <9.2% and with a limit of quantification (LoQ) of 25 nmol/l.…”

Section: Blood Sampling Handling and Drug Sample Analysismentioning

confidence: 99%

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

Simba

Kakoko

Tomson

et al. 2012

Transactions of the Royal Society of Tropical Medicine and Hygi

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a b s t r a c tA follow-up study was conducted to determine the magnitude of and factors related to adherence to artemether/lumefantrine (ALu) treatment in rural settings in Tanzania. Children in five villages of Kilosa District treated at health facilities were followed-up at their homes on Day 7 after the first dose of ALu. For those found to be positive using a rapid diagnostic test for malaria and treated with ALu, their caretakers were interviewed on drug administration habits. In addition, capillary blood samples were collected on Day 7 to determine lumefantrine concentrations. The majority of children (392/444; 88.3%) were reported to have received all doses, in time. Non-adherence was due to untimeliness rather than missing doses and was highest for the last two doses. No significant difference was found between blood lumefantrine concentrations among adherent (median 286 nmol/l) and nonadherent [median 261 nmol/l; range 25 nmol/l (limit of quantification) to 9318 nmol/l]. Children from less poor households were more likely to adhere to therapy than the poor [odds ratio (OR) = 2.45, 95% CI 1.35-4.45; adjusted OR = 2.23, 95% CI 1.20-4.13]. The high reported rate of adherence to ALu in rural areas is encouraging and needs to be preserved to reduce the risk of emergence of resistant strains. The age-based dosage schedule and lack of adherence to ALu treatment guidelines by health facility staff may explain both the huge variability in observed lumefantrine concentrations and the lack of difference in concentrations between the two groups.

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Section: Blood Sampling Handling and Drug Sample Analysismentioning

confidence: 99%

Section: Blood Sampling Handling and Drug Sample Analysismentioning

confidence: 99%

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

Simba

Kakoko

Tomson

et al. 2012

Transactions of the Royal Society of Tropical Medicine and Hygi

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“…Although previously considered only a putative metabolite of lumefantrine because of a lack of supportive pharmacokinetic data (20,24), recent analytical developments have enabled the reliable detection of relatively low concentrations of DBL in samples of plasma from small numbers of patients treated with conventional doses of artemether-lumefantrine combination therapy (11,15,18). The ratio of the maximum plasma concentration (C max ) of the parent compound to that of the metabolite in this situation has varied substantially, from 6 (18) to Ͼ270 (11).…”

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confidence: 99%

Desbutyl-Lumefantrine Is a Metabolite of Lumefantrine with Potent In Vitro Antimalarial Activity That May Influence Artemether-Lumefantrine Treatment Outcome

Wong

Salman

Ilett

et al. 2011

Antimicrob Agents Chemother

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Desbutyl-lumefantrine (DBL) is a metabolite of lumefantrine. Preliminary data from Plasmodium falciparum field isolates show greater antimalarial potency than, and synergy with, the parent compound and synergy with artemisinin. In the present study, the in vitro activity and interactions of DBL were assessed from tritiumlabeled hypoxanthine uptake in cultures of the laboratory-adapted strains 3D7 (chloroquine sensitive) and W2mef (chloroquine resistant). The geometric mean 50% inhibitory concentrations (IC 50 s) for DBL against 3D7 and W2mef were 9.0 nM (95% confidence interval, 5.7 to 14.4 nM) and 9.5 nM (95% confidence interval, 7.5 to 11.9 nM), respectively, and those for lumefantrine were 65.2 nM (95% confidence interval, 42.3 to 100.8 nM) and 55.5 nM (95% confidence interval, 40.6 to 75.7 nM), respectively. An isobolographic analysis of DBL and lumefantrine combinations showed no interaction in either laboratory-adapted strain but mild synergy between DBL and dihydroartemisinin (sums of the fractional inhibitory concentrations of 0.92 [95% confidence interval, 0.87 to 0.98] and 0.94 [95% confidence interval, 0.90 to 0.99] for 3D7 and W2mef, respectively). Using a validated ultra-high-performance liquid chromatography-tandem mass spectrometry assay and 94 day 7 samples from a previously reported intervention trial, the mean plasma DBL was 31.9 nM (range, 1.3 to 123.1 nM). Mean plasma DBL concentrations were lower in children who failed artemether-lumefantrine treatment than in those with an adequate clinical and parasitological response (ACPR) (P ‫؍‬ 0.053 versus P > 0.22 for plasma lumefantrine and the plasma lumefantrine-to-DBL ratio, respectively). DBL is more potent than the parent compound and mildly synergistic with dihydroartemisinin. These properties and the relationship between day 7 plasma concentrations and the ACPR suggest that it could be a useful alternative to lumefantrine as a part of artemisinin combination therapy.Desbutyl-lumefantrine (DBL) or desbutyl-benflumetol is a 2,3-benzindene compound with antimalarial activity. Although previously considered only a putative metabolite of lumefantrine because of a lack of supportive pharmacokinetic data (20,24), recent analytical developments have enabled the reliable detection of relatively low concentrations of DBL in samples of plasma from small numbers of patients treated with conventional doses of artemether-lumefantrine combination therapy (11,15,18). The ratio of the maximum plasma concentration (C max ) of the parent compound to that of the metabolite in this situation has varied substantially, from 6 (18) to Ͼ270 (11).DBL is more potent in vitro against chloroquine (CQ)-resistant Plasmodium falciparum and Plasmodium vivax field isolates than lumefantrine (13, 17, 23). There is evidence of in vitro synergy between lumefantrine and DBL against P. falciparum but at ratios (999:1 and 995:5) that were presumably selected at a time when plasma concentrations of DBL were assumed to be very much lower than those of the parent compound (23,24). Int...

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“…Dans ce but, nous avons vérifié les critères habituels de validation que sont la linéarité, la limite de détection, la préci-sion, l'exactitude et la spécificité [14]. En plus de ces critères, nous avons réalisé une épreuve de stabilité pour juger des possibilités de conservation de la luméfantrine dans des conditions de prélèvement et de transport difficiles.…”

Section: Validation Analytique De La Méthodeunclassified

“…L'étude de la littérature rapporte pour la luméfantrine plusieurs méthodes de dosages chromatographiques sur plasma [9][10][11] ou sur sang total [12]. Récem-ment, deux méthodes de dosage sur spot de sang séché ont été rapportées, permettant soit le dosage de la luméfantrine seule [13], soit de la molécule mère et de son métabolite [14].…”

Section: Introductionunclassified

Dosage par chromatographie liquide haute performance de la luméfantrine sur spot de sang séché

et al. 2009

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Résumé -Objectif : La luméfantrine, est un nouvel antipaludéen de synthèse utilisé en association avec l'artéméter dans le traitement de l'accès palustre simple chez l'enfant. Sa mauvaise biodisponibilité impose un suivi des concentrations circulantes pour identifier les échecs thérapeutiques qui sont dus à une mauvaise absorption de ceux qui résultent d'un phénomène de résistance. Nous avons développé le dosage de la luméfantrine sur spot de sang séché, support adapté au prélèvement et au stockage des échantillons dans des conditions difficiles. Méthodes : Le dosage de la luméfantrine a été réalisé par chromatographie liquide après extraction liquide-liquide des spots par le mélange acétate d'éthyle/acide acétique. La séparation est réalisée sur colonne Xbridge avec une phase acétate d'ammonium pH 4 / acétonitrile (10/90 v/v) en mode isocratique. La détection est réalisée en UV à 335 nm, avec le tocol comme étalon interne. Résultats : La luméfantrine et l'étalon interne sont élués en respectivement 7,1 et 10,3 minutes. La méthode est linéaire entre 250 et 5000 µg/L. La limite de détection est de 85 µg/L avec une limite de quantification à 250 µg/L. La précision est satisfaisante (< 10 %), de même que l'exactitude (biais < 10 %). Les spots sont stables à +4 • C pendant 10 jours, mais une conservation à +25 • C, s'accompagne d'une baisse significative des concentrations. Les concentrations résiduelles chez des enfants traités 3 jours par la luméfantrine sont de 490 ±152 µg/L. Conclusion : Nous rapportons une méthode robuste et fiable de dosage de la luméfantrine sur spots de sang séché applicable aux études pharmacocinétiques et épidémiologiques. Mots clés : Luméfantrine, CLHP, spot de sang séchéAbstract -Aim: Lumefantrine is a new anti-malarial drug used in association with artemeter in the treatment of uncomplicated Plasmodium falciparum malaria in children. Poor absorption of lumefantrine needs to monitor concentrations to identify the nature of the therapeutic failure. We have developed the determination of lumefantrine on dried blood spots, which are frequently used to collect and store blood in hard conditions. Methods: Lumefantrine measurement was assayed by liquid chromatography after liquid-liquid extraction procedure using ethyl acetate/acetic acid as solvent. Separation was performed on a Xbridge column using ammonium acetate pH 4 / acetonitrile (10/90 v/v) in isocratic mode. UV detection was set at 335 nm using tocol as internal standard. Results: Lumefantrine and internal standard are eluted at 7.1 and 10.3 min, respectively. The method is linear from 250 to 5000 µg/L with a good sensitivity corresponding to 85 µg/L for limit of detection and 250 µg/L as limit of quantification. Precision (below 10%) and accuracy (below 10%) are satisfying. Lumefantrine concentrations were stable in dried blood spot during 10 days at +4 • C but a significant decrease was observed at +25 • C. Blood residual concentrations in children treated by lumefantrine during 3 days were 490 ±152 µg/L. Conclusion: We have develop...

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A field-adapted sampling and HPLC quantification method for lumefantrine and its desbutyl metabolite in whole blood spotted on filter paper

Cited by 23 publications

References 24 publications

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

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

Desbutyl-Lumefantrine Is a Metabolite of Lumefantrine with Potent In Vitro Antimalarial Activity That May Influence Artemether-Lumefantrine Treatment Outcome

Dosage par chromatographie liquide haute performance de la luméfantrine sur spot de sang séché

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