Abstract

ABSTRACTThe artemether-lumefantrine combination requires food intake for the optimal absorption of lumefantrine. In an attempt to enhance the bioavailability of lumefantrine, new solid dispersion formulations (SDF) were developed, and the pharmacokinetics of two SDF variants were assessed in a randomized, open-label, sequential two-part study in healthy volunteers. In part 1, the relative bioavailability of the two SDF variants was compared with that of the conventional formulation after administration of a single dose of 480 mg under fasted conditions in three parallel cohorts. In part 2, the pharmacokinetics of lumefantrine from both SDF variants were evaluated after a single dose of 480 mg under fed conditions and a single dose of 960 mg under fasted conditions. The bioavailability of lumefantrine from SDF variant 1 and variant 2 increased up to ∼48-fold and ∼24-fold, respectively, relative to that of the conventional formulation. Both variants demonstrated a positive food effect and a less than proportional increase in exposure between the 480-mg and 960-mg doses. Most adverse events (AEs) were mild to moderate in severity and not suspected to be related to the study drug. All five drug-related AEs occurred in subjects taking SDF variant 2. No clinically significant treatment-emergent changes in vital signs, electrocardiograms, or laboratory blood assessments were noted. The solid dispersion formulation enhances the lumefantrine bioavailability to a significant extent, and SDF variant 1 is superior to SDF variant 2.

Highlights

  • The artemether-lumefantrine combination requires food intake for the optimal absorption of lumefantrine

  • Two new solid dispersion formulation (SDF) variants of lumefantrine were developed on the basis of preliminary data from studies with dogs under fasted conditions, in which an ϳ4-fold increase in BA relative to that of the conventional tablet was observed (Novartis, data on file)

  • In part 1, more adverse events (AEs) were reported with the solid dispersion formulations (SDF) variants (43.8% each, 7/16 subjects) than with the conventional tablets (18.8%, 3/16 subjects)

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Summary

Introduction

The artemether-lumefantrine combination requires food intake for the optimal absorption of lumefantrine. The bioavailability of lumefantrine from SDF variant 1 and variant 2 increased up to ϳ48-fold and ϳ24-fold, respectively, relative to that of the conventional formulation Both variants demonstrated a positive food effect and a less than proportional increase in exposure between the 480-mg and 960-mg doses. The overall cure rate for patients receiving artemether-lumefantrine is high, but there is significant variability in the levels of exposure because of differences in food intake, especially in ill patients. Two new solid dispersion formulation (SDF) variants of lumefantrine were developed on the basis of preliminary data from studies with dogs under fasted conditions, in which an ϳ4-fold increase in BA relative to that of the conventional tablet was observed (Novartis, data on file). The proportionality of a higher dose under fasting conditions was evaluated

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