title: Early clinical development of artemether-lumefantrine dispersible tablet: palatability of three flavours and bioavailability in healthy subjects.
abstract: BACKGROUND
  Efforts 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).
  
  
  METHODS
  Study 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).
  
  
  RESULTS
  Study 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 x 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.
  
  
  CONCLUSIONS
  Considering 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.
authors.affiliation: Ifakara Health Institute, Ifakara and Dar es Salaam, Tanzania. sabdulla@ihi.or.tz
authors.forename: Salim
authors.initials: S
authors.lastname: Abdulla
authors.forename: Baraka
authors.initials: B
authors.lastname: Amuri
authors.forename: Abdunoor M
authors.initials: AM
authors.lastname: Kabanywanyi
authors.forename: David
authors.initials: D
authors.lastname: Ubben
authors.forename: Christine
authors.initials: C
authors.lastname: Reynolds
authors.forename: Steve
authors.initials: S
authors.lastname: Pascoe
authors.forename: Serge
authors.initials: S
authors.lastname: Fitoussi
authors.forename: Ching-Ming
authors.initials: CM
authors.lastname: Yeh
authors.forename: Marja
authors.initials: M
authors.lastname: Nuortti
authors.forename: Romain
authors.initials: R
authors.lastname: Séchaud
authors.forename: Günther
authors.initials: G
authors.lastname: Kaiser
authors.forename: Gilbert
authors.initials: G
authors.lastname: Lefèvre
mesh_terms: D000328:Adult; D000962:Antimalarials / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001682:Biological Availability; D002648:Child; D018592:Cross-Over Studies; D004338:Drug Combinations; D004983:Ethanolamines / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D005260:Female; D005421:Flavoring Agents / Q000008:administration & dosage; D005449:Fluorenes / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D006805:Human Experimentation; D006801:Humans; D008297:Male; D013607:Tablets / Q000008:administration & dosage; D013636:Tanzania
chemical_list: D000962:Antimalarials; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins; D004338:Drug Combinations; D004983:Ethanolamines; D005421:Flavoring Agents; D005449:Fluorenes; D013607:Tablets; C039060:artenimol
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