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Lower artemether, dihydroartemisinin and lumefantrine concentrations during rifampicin-based tuberculosis treatment.

Lamorde M., Byakika-Kibwika P., Mayito J., Nabukeera L., Ryan M., Hanpithakpong W., Lefèvre G., Back DJ., Khoo SH., Merry C.

ObjectiveTo investigate the pharmacokinetics of artemether, dihydroartemisinin and lumefantrine during rifampicin intake and after stopping rifampicin.Study designAn open-label, two-phase, longitudinal drug interaction study with patients serving as their own controls.MethodsWe recruited HIV-1-seropositive Ugandan adults who were receiving rifampicin-based tuberculosis treatment and who did not have malaria. Pharmacokinetic sampling after six doses of artemether-lumefantrine was performed during rifampicin-based tuberculosis treatment (phase 1) and repeated at least 3 weeks after stopping rifampicin-based tuberculosis treatment (phase 2).ResultsSix and five patients completed phases 1 and 2, respectively. Median age and weight were 30 years and 64 kg. Artemether and dihydroartemisinin area under the concentration-time curve (AUC(0-12h)) were significantly lower by 89% [geometric mean ratio (GMR) 90% confidence interval (CI) 0.11, 0.05-0.26] and 85% (0.15, 0.10-0.23), respectively, during rifampicin-based treatment when compared to AUC(0-12h) after stopping rifampicin intake. Similarly, artemether and dihydroartemisinin C(max) were 83% (0.17, 0.08-0.39) and 78% (0.22, 0.15-0.33) lower, respectively, during rifampicin treatment. For artemether, mean (±SD) C(12) was 0.5(±1.0) and 5.9(±2.5) ng/ml in phases 1 and 2, respectively. Corresponding values for dihydroartemisinin (DHA) were 0.3(±0.4) and 4.7(±2.0) ng/ml, respectively. Day 8 lumefantrine concentration was significantly lower by 84% (GMR 90% CI 0.16, 0.09-0.27), and AUC(Day3-Day25) was significantly lower by 68% (GMR 90% CI 0.32, 0.21-0.49) during rifampicin-based treatment when compared to exposure values after stopping rifampicin.ConclusionPharmacokinetic parameters for artemether-lumefantrine were markedly lower during rifampicin-based tuberculosis treatment. Artemether-lumefantrine should not be co-administered with rifampicin.

More information Original publication

DOI

10.1097/qad.0b013e32835cae3b

Type

Journal article

Publication Date

2013-03-01T00:00:00+00:00

Volume

27

Pages

961 - 965

Total pages

4

Addresses

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Keywords

Humans, Tuberculosis, HIV Infections, Ethanolamines, Artemisinins, Rifampin, Fluorenes, Antitubercular Agents, Antimalarials, Longitudinal Studies, Drug Antagonism, Adult, Uganda, Female, Male, Artemether, Lumefantrine