title: Correlation of plasma anti-tuberculosis drug levels with subsequent development of hepatotoxicity.
abstract: OBJECTIVE
  To compare the free and total plasma drug concentrations of rifampicin (RMP), isoniazid and pyrazinamide in subjects with or without anti-tuberculosis drug-induced hepatotoxicity (DIH).
  
  
  METHODS
  A total of 110 tuberculosis (TB) patients were administered daily anti-tuberculosis treatment and were prospectively followed for the development of DIH. Plasma drug levels were measured at 0, 1, 2 and 4 h on days 1, 7 and 14 of treatment. Plasma drug levels in 15 patients who developed DIH (cases) were compared with 95 patients who did not (controls).
  
  
  RESULTS
  Female sex, body mass index < 17 kg/m(2) and baseline serum albumin < 4 g/dl predicted risk of DIH on univariate analyses. Free and total plasma RMP levels (Cmax and AUC0-4) on days 1, 7 and 14 were significantly higher in cases compared to controls and predicted development of DIH. Day 7 total RMP Cmax and AUC0-4 were higher in cases (mean 26.73, standard deviation [SD] 5.72 and 47.58, SD 33.10) than in controls (7.87, SD 10.95 and 14.01, SD 10.69, respectively).
  
  
  CONCLUSIONS
  Plasma RMP levels were higher in cases than in controls and independently predicted subsequent development of DIH. The Cmax of Day 7 total RMP level (cut-off 12.50 mg/l) predicted subsequent development of DIH in 93.3% of the patients.
authors.affiliation: Department of Medicine, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: A
authors.initials: A
authors.lastname: Satyaraddi
authors.affiliation: Department of Ocular Pharmacology and Pharmacy, Dr Rajender Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: T
authors.initials: T
authors.lastname: Velpandian
authors.affiliation: Department of Medicine, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: S K
authors.initials: SK
authors.lastname: Sharma
authors.affiliation: Department of Biostatistics, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: S
authors.initials: S
authors.lastname: Vishnubhatla
authors.affiliation: Medical University, Pleven, Bulgaria.
authors.forename: A
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Department of Ophthalmology, Dr Rajender Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: A
authors.initials: A
authors.lastname: Sirohiwal
authors.affiliation: Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: G K
authors.initials: GK
authors.lastname: Makharia
authors.affiliation: Department of Medicine, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: S
authors.initials: S
authors.lastname: Sinha
authors.affiliation: Department of Medicine, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: A
authors.initials: A
authors.lastname: Biswas
authors.affiliation: Department of Laboratory Medicine, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: S
authors.initials: S
authors.lastname: Singh
mesh_terms: D000328:Adult; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood* / Q000493:pharmacokinetics; D019540:Area Under Curve; D016022:Case-Control Studies; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood* / Q000209:etiology*; D004334:Drug Administration Schedule; D016903:Drug Monitoring; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007538:Isoniazid / Q000009:adverse effects / Q000097:blood; D008297:Male; D008657:Metabolic Clearance Rate; D011446:Prospective Studies; D011718:Pyrazinamide / Q000009:adverse effects / Q000097:blood; D012293:Rifampin / Q000009:adverse effects / Q000097:blood; D012307:Risk Factors; D014376:Tuberculosis / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D011718:Pyrazinamide; D007538:Isoniazid; D012293:Rifampin