Bioavailability of Lumefantrine Is Significantly Enhanced with a Novel Formulation Approach, an Outcome from a Randomized, Open-Label Pharmacokinetic Study in Healthy Volunteers

Abstract

The 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.

A Randomized Controlled Trial of Three- versus Five-Day Artemether-Lumefantrine Regimens for Treatment of Uncomplicated Plasmodium falciparum Malaria in Pregnancy in Africa

“…In daily clinical practice, adherence to a 5-day treatment and coadministration with fatty foods might be suboptimal. A new solid-dispersion formulation of lumefantrine is currently under development by Novartis (30). The preliminary results showed a significant improvement in drug bioavailability in healthy subjects.…”

In vivo/ex vivo efficacy of artemether–lumefantrine and artesunate–amodiaquine as first-line treatment for uncomplicated falciparum malaria in children: an open label randomized controlled trial in Burkina Faso

“…These post treatment prophylactic effects are mainly related to the elimination half-life of the partner drug. Lumefantrine has the shortest elimination half-life (3-5 days) [50], then followed by monodesethylamodiaquine (10-18 days) [51], and could be the reason behind the better efficacy of artesunate plus amodiaquine. However, a prolonged elimination and protection time may drive the development of resistance in a setting of high malaria transmission due to frequent and longer exposition of parasite to decreased drug concentration level in patient blood [52].…”

Old and Recent Advances in Life Cycle, Pathogenesis, Diagnosis, Prevention, and Treatment of Malaria Including Perspectives in Ethiopia

“…KAF156 (class of imidazolopiperazines) is with potential to treat and prevent malaria since it acts at multistage of the parasite life cycle [192,193]. is drug is now joined phase IIb trial in combination with lumefantrine [194,195].…”

“…DSM265 is another compound in phase II trial that inhibits falciparum dihydroorotate dehydrogenase (PfDHODH) and vivax dihydroorotate dehydrogenase (PvDHODH) enzymes [195]. is new chemical is a long acting with blood and liver stage activity [193].…”