Pharmacokinetics and electrocardiographic pharmacodynamics of artemether‐lumefantrine (Riamet^®) with concomitant administration of ketoconazole in healthy subjects

Abstract

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 m g ml -1 h (ratio 1.7, 90% CI 1.23, 2.21) for lumefantrine in the presence of ketoconazole. C max 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.

Interaction between Artemether-Lumefantrine and Nevirapine-Based Antiretroviral Therapy in HIV-1-Infected Patients

“…However, malaria illness could attenuate the autoinduction seen in our clinically well HIV-infected patients and in previously described studies on healthy volunteers. Artemether and dihydroartemisinin exposure in our ART-naïve group is similar to previously published results in healthy volunteer studies (15,21), suggesting that there is not a marked HIV disease effect.…”

Population Pharmacokinetics of Lumefantrine in Pregnant Women Treated with Artemether-Lumefantrine for Uncomplicated Plasmodium falciparum Malaria

“…Artemether is metabolized by the cytochrome P450 (CYP450) enzymes CYP1A2, CYP2B6, CYP2C19, and CYP3A4 in vitro (38); but no contribution by CYP2C19 could be seen in healthy volunteers (48). Lumefantrine is mainly metabolized by CYP3A4 (26)(27)(28). In vitro studies have shown that CYP2A6 is the most important CYP450 enzyme in the metabolism of nicotine (36,37).…”

Functional Characterization of CYP2B6 Allelic Variants in Demethylation of Antimalarial Artemether

“…The conversion of AM to DHA is catalyzed by cytochrome P450 (P450) (van Agtmael et al, 1999b,c;Navaratnam et al, 2000). However, the elimination half-life of AM is very short, and it shows large interindividual variability in pharmacokinetic parameters (Na Bangchang et al, 1994;Mordi et al, 1997;van Agtmael et al, 1999a;Lefèvre et al, 2002;Ali et al, 2010;Mwesigwa et al, 2010).…”