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

Lamorde, Mohammeda,b; Byakika-Kibwika, Paulinea,b,c; Mayito, Jonathana; Nabukeera, Lilliana; Ryan, Mairinb; Hanpithakpong, Waruneed; Lefèvre, Gilberte; Back, David J.f; Khoo, Saye H.f; Merry, Conceptaa,b,g

doi: 10.1097/QAD.0b013e32835cae3b
Clinical Science: Concise Communications

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 (AUC0–12h) 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 AUC0–12h after stopping rifampicin intake. Similarly, artemether and dihydroartemisinin Cmax 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) C12 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 AUCDay3-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.

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.

Correspondence to Mohammed Lamorde, MBBS, MRCP, PhD, Infectious Diseases Institute, Makerere University College of Health Sciences, P.O. Box 22418, Kampala, Uganda. Tel: +256 414 307291; fax: +256 414 307290; e-mail: mlamorde@idi.co.ug

Received 13 September, 2012

Revised 5 November, 2012

Accepted 15 November, 2012

© 2013 Lippincott Williams & Wilkins, Inc.