Early clinical development of artemether-lumefantrine dispersible tablet: palatability of three flavours and bioavailability in healthy subjects

Salim Abdulla,Baraka Amuri,Christine Reynolds,Ching-Ming Yeh,Marja Nuortti,Steve Pascoe,Günther Kaiser,David Ubben,Gilbert Lefèvre,Serge Fitoussi,Romain Séchaud,Abdunoor M Kabanywanyi

doi:10.1186/1475-2875-9-253

Abstract

BackgroundEfforts to ease administration and enhance acceptability of the oral anti-malarial artemether-lumefantrine (A-L) crushed tablet to infants and children triggered the development of a novel dispersible tablet of A-L. During early development of this new formulation, two studies were performed in healthy subjects, one to evaluate the palatability of three flavours of A-L, and a second one to compare the bioavailability of active principles between the dispersible tablet and the tablet (administered crushed and intact).MethodsStudy 1 was performed in 48 healthy schoolchildren in Tanzania. Within 1 day, all subjects tasted a strawberry-, orange- and cherry-flavoured oral A-L suspension for 10 seconds (without swallowing) in a randomized, single-blind, crossover fashion. The palatability of each formulation was rated using a visual analogue scale (VAS). Study 2 was an open, randomized crossover trial in 48 healthy adults given single doses of A-L (80 mg artemether + 480 mg lumefantrine) with food. The objectives were to compare the bioavailability of artemether, dihydroartemisinin (DHA) and lumefantrine between the dispersible tablet and the tablet administered crushed (primary objective) and intact (secondary objective).ResultsStudy 1 showed no statistically significant difference in VAS scores between the three flavours but cherry had the highest score in several ratings (particularly for overall liking). Study 2 demonstrated that the dispersible and crushed tablets delivered bioequivalent artemether, DHA and lumefantrine systemic exposure (area under the curve [AUC]); mean ± SD AUC0-tlast were 208 ± 113 vs 195 ± 93 h.ng/ml for artemether, 206 ± 81 vs 199 ± 84 h.ng/ml for DHA and 262 ± 107 vs 291 ± 106 h.μg/ml for lumefantrine. Bioequivalence was also shown for peak plasma concentrations (Cmax) of DHA and lumefantrine. Compared with the intact tablet, the dispersible tablet resulted in bioequivalent lumefantrine exposure, but AUC and Cmax values of artemether and DHA were 20-35% lower.ConclusionsConsidering that cherry was the preferred flavour, and that the novel A-L dispersible tablet demonstrated similar pharmacokinetic performances to the tablet administered crushed, a cherry-flavoured A-L dispersible tablet formulation was selected for further development and testing in a large efficacy and safety study in African children with malaria.

Highlights

Efforts to ease administration and enhance acceptability of the oral anti-malarial artemetherlumefantrine (A-L) crushed tablet to infants and children triggered the development of a novel dispersible tablet of A-L
During early clinical development of A-L dispersible tablet, one study investigated the palatability of three flavours of A-L in healthy African schoolchildren using an oral suspension formulation prepared immediately prior to tasting from powder-in-bottle suspended with water
The principal findings of these two studies can be summarized as follows: (1) All three tested flavours appeared appropriate to improve the taste of A-L but cherry was overall preferred by children; (2) exposure to artemether, DHA and lumefantrine was comparable for the dispersible and crushed tablet formulations in healthy adults; and (3) there were differences of the same magnitude in the exposure to artemether and DHA between the dispersible tablet and the intact tablet, and between the crushed and intact tablets in adult healthy subjects, while exposure to lumefantrine was similar in these comparisons

Summary

Introduction

Efforts to ease administration and enhance acceptability of the oral anti-malarial artemetherlumefantrine (A-L) crushed tablet to infants and children triggered the development of a novel dispersible tablet of A-L. In 2004, the A-L tablet (Coartem® ) became the first fixed-dose ACT to be prequalified by the World Health Organization, and received approval from the Food and Drug Administration in the US in April 2009 [6]. This tablet formulation, containing 20 mg of artemether and 120 mg of lumefantrine, has been proven to be efficacious and safe in the treatment of uncomplicated Plasmodium falciparum malaria when administered in a six-dose regimen for 3 days [7,8]. The pharmacokinetic features of artemether and lumefantrine are similar in children, when dosed according to their body weight, compared with adults [13]

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