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OBJECTIVE:To investigate the pharmacokinetics of artemether, dihydroartemisinin and lumefantrine during rifampicin intake and after stopping rifampicin. STUDY DESIGN:An open-label, two-phase, longitudinal drug interaction study with patients serving as their own controls. METHODS:We 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). RESULTS:Six 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. CONCLUSION:Pharmacokinetic parameters for artemether-lumefantrine were markedly lower during rifampicin-based tuberculosis treatment. Artemether-lumefantrine should not be co-administered with rifampicin.

Original publication

DOI

10.1097/qad.0b013e32835cae3b

Type

Journal article

Journal

AIDS (London, England)

Publication Date

03/2013

Volume

27

Pages

961 - 965

Addresses

aInfectious Diseases Institute, Makerere University College of Health Sciences, Kampala, Uganda bDepartment of Pharmacology and Therapeutics, Trinity College Dublin, Ireland cInfectious Diseases Network for Treatment and Research in Africa, Kampala, Uganda dMahidol University-Oxford University Research Unit, Faculty of Tropical Medicine, Mahidol University, Thailand eNovartis Pharma AG, Basel, Switzerland fDepartment of Molecular and Clinical Pharmacology, University of Liverpool, UK gDepartment of Genitourinary Medicine, St James's Hospital, Dublin, Ireland.

Keywords

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