Abstract
Mefloquine-artesunate is a formulation of artemisinin based combination therapy (ACT) recommended by the World Health Organization and historically the first ACT used clinically. The use of ACT demands constant monitoring of therapeutic efficacies and drug levels, in order to ensure that optimum drug exposure is achieved and detect reduced susceptibility to these drugs. Quantification of anti-malarial drugs in biological fluids other than blood would provide a more readily applicable method of therapeutic drug monitoring in developing endemic countries. Efforts in this study were devoted to the development of a simple, field applicable, non-invasive method for assay of mefloquine in saliva. A high performance liquid chromatographic method with UV detection at 220 nm for assaying mefloquine in saliva was developed and validated by comparing mefloquine concentrations in saliva and plasma samples from four healthy volunteers who received single oral dose of mefloquine. Verapamil was used as internal standard. Chromatographic separation was achieved using a Hypersil ODS column. Extraction recoveries of mefloquine in plasma or saliva were 76-86% or 83-93% respectively. Limit of quantification of mefloquine was 20 ng/ml. Agreement between salivary and plasma mefloquine concentrations was satisfactory (r = 0.88, p < 0.001). Saliva:plasma concentrations ratio was 0.42. Disposition of mefloquine in saliva paralleled that in plasma, making salivary quantification of mefloquine potentially useful in therapeutic drug monitoring.
Highlights
Mefloquine-artesunate is a formulation of artemisinin based combination therapy (ACT) recommended by the World Health Organization and historically the first ACT used clinically
The separation chromatograms of mefloquine and the internal standard from spiked plasma or saliva samples (Figure 1) corresponded with those of plasma or saliva samples obtained from a healthy volunteer 6 hr after an oral dose of mefloquine (Figure 2)
The extraction recoveries for 400 ng/ml, 800 ng/ml and 1,000 ng/ml of mefloquine in plasma or saliva were 75.7 ± 6.2% vs 83.3 ± 5.6%, 79.2 ± 4.2% vs 91.3 ± 1.7% and 86.2 ± 2.0% vs 92.8 ± 2.0% (n = 4) respectively
Summary
Mefloquine-artesunate is a formulation of artemisinin based combination therapy (ACT) recommended by the World Health Organization and historically the first ACT used clinically. The combination non-artemisinin partner drug maintains consistent pharmacokinetic and pharmacodynamic properties Based on this backdrop, the use of ACT demands constant monitoring of therapeutic efficacies and drug levels, in order to ensure that optimum drug exposure is achieved with the dosing strategy and detect reduced susceptibility to these drugs. Anti-malarial drug levels have been measured in biological fluids such as whole blood, plasma or red blood cells [2,6,7,8,9,10,11] obtained by invasive techniques This method of sampling poses challenges in resource poor settings and during epidemiological studies where repeated measurements are required. The unbound fraction of a drug is usually the pharmacologically active fraction and this may represent an advantage of drug monitoring in saliva in comparison with drug monitoring in serum where both bound and unbound drug can be detected [15]
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