title: Clinical significance of 2 h plasma concentrations of first-line anti-tuberculosis drugs: a prospective observational study.
abstract: OBJECTIVE
  To study 2 h plasma concentrations of the first-line tuberculosis drugs isoniazid, rifampicin, ethambutol and pyrazinamide in a cohort of patients with tuberculosis in Denmark and to determine the relationship between the concentrations and the clinical outcome.
  
  
  METHODS
  After 6-207 days of treatment (median 34 days) 2 h blood samples were collected from 32 patients with active tuberculosis and from three patients receiving prophylactic treatment. Plasma concentrations were determined using LC-MS/MS. Normal ranges were obtained from the literature. Clinical charts were reviewed for baseline characteristics and clinical status at 2, 4 and 6 months after the initiation of treatment. At a 1 year follow-up, therapy failure was defined as death or a relapse of tuberculosis.
  
  
  RESULTS
  Plasma concentrations below the normal ranges were frequently observed: isoniazid in 71%, rifampicin in 58%, ethambutol in 46%, pyrazinamide in 10% and both isoniazid and rifampicin in 45% of the patients. The plasma concentrations of isoniazid correlated inversely with the C-reactive protein level at the time of sampling (P = 0.001). During 1 year of follow-up, therapy failure occurred in five patients. Therapy failure occurred more frequently when the concentrations of isoniazid and rifampicin were both below the normal ranges (P = 0.013) and even more frequently when they were below the median 2 h drug concentrations obtained in the study (P = 0.005).
  
  
  CONCLUSIONS
  At 2 h, plasma concentrations of isoniazid and rifampicin below the normal ranges were frequently observed. The inverse correlation between the plasma concentrations of isoniazid and C-reactive protein indicate a suboptimal treatment effect at standard dosing regimens. Dichotomization based on median 2 h drug concentrations was more predictive of outcome than dichotomization based on normal ranges.
authors.affiliation: International Reference Laboratory of Mycobacteriology, Statens Serum Institut, 5 Artillerivej, 2300 Copenhagen, Denmark jpl@ssi.dk.
authors.forename: Julie B
authors.initials: JB
authors.lastname: Prahl
authors.affiliation: Department of Infectious Diseases, Copenhagen University Hospital Hvidovre, Kettegård Alle 30, 2650 Hvidovre, Denmark.
authors.forename: Isik S
authors.initials: IS
authors.lastname: Johansen
authors.affiliation: Department of Biochemistry, Immunology and Genetics, Statens Serum Institut, 5 Artillerivej, 2300 Copenhagen, Denmark.
authors.forename: Arieh S
authors.initials: AS
authors.lastname: Cohen
authors.affiliation: Department of Clinical Microbiology, Copenhagen University Hospital Hvidovre, Kettegård Alle 30, 2650 Hvidovre, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Frimodt-Møller
authors.affiliation: Department of Infectious Diseases, Copenhagen University Hospital Rigshospitalet, 9 Blegdamsvej, 2100 Copenhagen Ø, Denmark.
authors.forename: Åse B
authors.initials: ÅB
authors.lastname: Andersen
mesh_terms: D000328:Adult; D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D008297:Male; D011446:Prospective Studies; D012307:Risk Factors; D013997:Time Factors; D017211:Treatment Failure; D016896:Treatment Outcome; D014376:Tuberculosis / Q000175:diagnosis / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents
keywords: anti-tuberculosis drugs; therapeutic drug monitoring; tuberculosis