title: Impact of food on the pharmacokinetics of first-line anti-TB drugs in treatment-naive TB patients: a randomized cross-over trial.
abstract: OBJECTIVE
  Concomitant food intake influences pharmacokinetics of first-line anti-TB drugs in healthy volunteers. However, in treatment-naive TB patients who are starting with drug treatment, data on the influence of food intake on the pharmacokinetics are absent. This study aimed to quantify the influence of food on the pharmacokinetics of isoniazid, rifampicin, ethambutol and pyrazinamide in TB patients starting anti-TB treatment.
  
  
  METHODS
  A prospective randomized cross-over pharmacokinetic study was conducted in treatment-naive adults with drug-susceptible TB. They received isoniazid, rifampicin and ethambutol intravenously and oral pyrazinamide on day 1, followed by oral administration of these drugs under fasted and fed conditions on two consecutive days. Primary outcome was the bioavailability while fasting and with concomitant food intake. This study was registered with clinicaltrials.gov identifier NCT02121314.
  
  
  RESULTS
  Twenty subjects completed the study protocol. Absolute bioavailability in the fasted state and the fed state was 93% and 78% for isoniazid, 87% and 71% for rifampicin and 87% and 82% for ethambutol. Food decreased absolute bioavailability of isoniazid and rifampicin by 15% and 16%, respectively. Pyrazinamide AUC0-24 was comparable for the fasted state (481 mg·h/L) and the fed state (468 mg·h/L). Food lowered the maximum concentrations of isoniazid, rifampicin and pyrazinamide by 42%, 22% and 10%, respectively. Time to maximum concentration was delayed for isoniazid, rifampicin and pyrazinamide. The pharmacokinetics of ethambutol were unaffected by food.
  
  
  CONCLUSIONS
  Food decreased absolute bioavailability and maximum concentration of isoniazid and rifampicin, but not of ethambutol or pyrazinamide, in treatment-naive TB patients. In patients prone to low drug exposure, this may further compromise treatment efficacy and increase the risk of acquired drug resistance.
authors.affiliation: Department of Internal Medicine, Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, Indonesia Department of Pulmonary Diseases and Tuberculosis, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Antonia M I
authors.initials: AM
authors.lastname: Saktiawati
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Marieke G G
authors.initials: MG
authors.lastname: Sturkenboom
authors.affiliation: Department of Internal Medicine/Infectious Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Ymkje
authors.initials: Y
authors.lastname: Stienstra
authors.affiliation: Department of Internal Medicine, Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, Indonesia.
authors.forename: Yanri W
authors.initials: YW
authors.lastname: Subronto
authors.affiliation: Department of Internal Medicine, Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, Indonesia.
authors.lastname: Sumardi
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands Section of Pharmacotherapy and Pharmaceutical Care, Department of Pharmacy, University of Groningen, Groningen, The Netherlands.
authors.forename: Jos G W
authors.initials: JG
authors.lastname: Kosterink
authors.affiliation: Department of Pulmonary Diseases and Tuberculosis, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands Department of Internal Medicine/Infectious Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Tjip S
authors.initials: TS
authors.lastname: van der Werf
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands j.w.c.alffenaar@umcg.nl.
authors.forename: Jan-Willem C
authors.initials: JW
authors.lastname: Alffenaar
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D000328:Adult; D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D004435:Eating; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents