Evaluation of two novel tablet formulations of artemether-lumefantrine (Coartem®) for bioequivalence in a randomized, open-label, two-period study

Background: Artemether-lumefantrine (Coartem (R); AL) is a standard of care for malaria treatment as an oral six-dose regimen, given twice daily over three days with one to four tablets (20/120 mg) per dose, depending on patient body weight. In order to reduce the pill burden at each dose and potentially enhance compliance, two novel fixed-dose tablet formulations (80/480 mg and 60/360 mg) have been developed and tested in this study for bioequivalence with their respective number of standard tablets. Methods: A randomized, open-label, two-period, single-dose, within formulation crossover bioequivalence study comparing artemether and lumefantrine exposure between the novel 80/480 mg tablet and four standard tablets, and the novel 60/360 mg tablet and three standard tablets, was conducted in 120 healthy subjects under fed conditions. Artemether, dihydroartemisinin, and lumefantrine were measured in plasma by HPLC/UPLC-MS/MS. Pharmacokinetic (PK) parameters were determined by non-compartmental analyses. Results: Adjusted geometric mean AUC(last) for artemether were 345 and 364 ng.h/mL (geometric mean ratio (GMR) 0.95; 90% CI 0.89-1.01) and for lumefantrine were 219 and 218 mu g.h/mL (GMR 1.00; 90% CI 0.93-1.08) for 80/480 mg tablet versus four standard tablets, respectively. Corresponding C-max for artemether were 96.8 and 99.7 ng/mL (GMR 0.97; 90% CI 0.89-1.06) and for lumefantrine were 8.42 and 8.71 mu g/mL (GMR 0.97; 90% CI 0.89-1.05). For the 60/360 mg tablet versus three standard tablets, adjusted geometric mean AUC(last) for artemether were 235 and 231 ng.h/mL (GMR 1.02; 90% CI 0.94-1.10), and for lumefantrine were 160 and 180 mu g.h/mL (GMR 0.89; 90% CI 0.83-0.96), respectively. Corresponding C-max for artemether were 75.5 and 71.5 ng/mL (GMR 1.06; 90% CI 0.95-1.18), and for lumefantrine were 6.64 and 7.61 mu g/mL (GMR 0.87; 90% CI 0.81-0.94), respectively. GMR for C-max and AUC(last) for artemether and lumefantrine for all primary comparisons were within the bioequivalence acceptance criteria (0.80-1.25). In addition, secondary PK parameters also met bioequivalence criterion. Conclusion: Both of the novel artemether-lumefantrine tablet formulations evaluated are bioequivalent to their respective standard Coartem (R) tablet doses. These novel formulations are easy to administer and may improve adherence in the treatment of uncomplicated malaria caused by Plasmodium falciparum.