Pharmacokinetics and electrocardiographic pharmacodynamics of artemether-lumefantrine (Riamet®) with concomitant administration of ketoconazole in healthy subjects
Article first published online: 11 NOV 2002
British Journal of Clinical Pharmacology
Volume 54, Issue 5, pages 485–492, November 2002
How to Cite
Lefèvre, G., Carpenter, P., Souppart, C., Schmidli, H., McClean, M. and Stypinski, D. (2002), Pharmacokinetics and electrocardiographic pharmacodynamics of artemether-lumefantrine (Riamet®) with concomitant administration of ketoconazole in healthy subjects. British Journal of Clinical Pharmacology, 54: 485–492. doi: 10.1046/j.1365-2125.2002.01696.x
- Issue published online: 11 NOV 2002
- Article first published online: 11 NOV 2002
- Accepted 19 February 2002.
Aims To evaluate whether the potent CYP3A4 inhibitor ketoconazole has any influence on the pharmacokinetic and electrocardiographic parameters of the antimalarial co-artemether (artemether-lumefantrine) in healthy subjects.
Methods Sixteen subjects were randomized in an open-label, two period crossover design study. Subjects received a single dose of co-artemether (day 1) either alone or in combination with multiple oral doses of ketoconazole (400 mg on day 1 followed by 200 mg o.d. for 4 additional days). Serial blood samples were taken and assayed for artemether and its main active metabolite dihydroartemisinin (DHA), and lumefantrine.
Results The pharmacokinetics of artemether, its metabolite DHA, and lumefantrine were influenced by the presence of ketoconazole. AUC(0,∞) was increased from 320 to 740 ng ml−1 h (ratio 2.4, 90% CI 2.00, 2.86) for artemether, from 331 to 501 ng ml−1 h (ratio 1.7, 90% CI 1.40, 1.98) for DHA, and from 207 to 333 µg ml−1 h (ratio 1.7, 90% CI 1.23, 2.21) for lumefantrine in the presence of ketoconazole. Cmax also increased in similar proportions for the three compounds (ratio 2.2 (90% CI 1.78, 2.83), 1.4 (90% CI 1.12, 1.74), and 1.3 (90% CI 0.96, 1.64), respectively). The terminal elimination half-life was increased for artemether (2.5 vs 1.9 h, 90% CI 1.12, 1.72) and DHA (3.1 vs 2.1 h, 90% CI 0.02, 3.36), but remained unchanged for lumefantrine (88 vs 95 h, 90% CI 0.81, 1.04). These increases in exposure to the antimalarial combination were much smaller than observed with food intake (up to 16 fold), and were not associated with increased side-effects or changes in electrocardiographic parameters. The study medications were well tolerated.
Conclusions The concurrent administration of ketoconazole with co-artemether led to modest increases in artemether, DHA, and lumefantrine exposure in healthy subjects. Dose adjustment of co-artemether is probably unnecessary in falciparum malaria patients when administered in association with ketoconazole or other potent CYP3A4 inhibitors.