title: Lower artemether, dihydroartemisinin and lumefantrine concentrations during rifampicin-based tuberculosis treatment.
abstract: OBJECTIVE
  To investigate the pharmacokinetics of artemether, dihydroartemisinin and lumefantrine during rifampicin intake and after stopping rifampicin.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  Pharmacokinetic parameters for artemether-lumefantrine were markedly lower during rifampicin-based tuberculosis treatment. Artemether-lumefantrine should not be co-administered with rifampicin.
authors.affiliation: 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.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Lamorde
authors.forename: Pauline
authors.initials: P
authors.lastname: Byakika-Kibwika
authors.forename: Jonathan
authors.initials: J
authors.lastname: Mayito
authors.forename: Lillian
authors.initials: L
authors.lastname: Nabukeera
authors.forename: Mairin
authors.initials: M
authors.lastname: Ryan
authors.forename: Warunee
authors.initials: W
authors.lastname: Hanpithakpong
authors.forename: Gilbert
authors.initials: G
authors.lastname: Lefèvre
authors.forename: David J
authors.initials: DJ
authors.lastname: Back
authors.forename: Saye H
authors.initials: SH
authors.lastname: Khoo
authors.forename: Concepta
authors.initials: C
authors.lastname: Merry
mesh_terms: D000328:Adult; D000962:Antimalarials / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000077549:Artemether; D037621:Artemisinins / Q000008:administration & dosage / Q000493:pharmacokinetics; D004336:Drug Antagonism; D004983:Ethanolamines / Q000008:administration & dosage / Q000493:pharmacokinetics; D005260:Female; D005449:Fluorenes / Q000008:administration & dosage / Q000493:pharmacokinetics; D015658:HIV Infections / Q000150:complications; D006801:Humans; D008137:Longitudinal Studies; D000078102:Lumefantrine; D008297:Male; D012293:Rifampin / Q000008:administration & dosage / Q000493:pharmacokinetics; D014376:Tuberculosis / Q000150:complications / Q000188:drug therapy*; D014454:Uganda
chemical_list: D000962:Antimalarials; D000995:Antitubercular Agents; D037621:Artemisinins; D004983:Ethanolamines; D005449:Fluorenes; C039060:artenimol; D000077549:Artemether; D000078102:Lumefantrine; D012293:Rifampin