Pharmacokinetics and electrocardiographic pharmacodynamics of artemether-lumefantrine (Riamet) with concomitant administration of ketoconazole in healthy subjects.
OBJECTIVE
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, infinity ) 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 micro g 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.
Lefèvre
Gilbert
G
Clinical Pharmacology, Novartis Pharma Ltd, WSJ-27.3.102, CH-4002 Basel, Switzerland. gilbert.lefevre@pharma.novartis.com
Carpenter
Polly
P
Souppart
Claire
C
Schmidli
Heinz
H
McClean
Mark
M
Stypinski
Daria
D
D000328:Adult; D000962:Antimalarials / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D018592:Cross-Over Studies; D004338:Drug Combinations; D004562:Electrocardiography / Q000187:drug effects; D004983:Ethanolamines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D005260:Female; D005449:Fluorenes / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007654:Ketoconazole / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D000078102:Lumefantrine; D008297:Male; D008875:Middle Aged; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D013997:Time Factors
D000962:Antimalarials; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins; D004338:Drug Combinations; D004983:Ethanolamines; D005449:Fluorenes; D012717:Sesquiterpenes; D000078102:Lumefantrine; D007654:Ketoconazole