title: Might isoniazid plasma exposure be a valuable predictor of drug-related hepatotoxicity risk among adult patients with TB?
abstract: OBJECTIVE
  To investigate the relationship between isoniazid plasma exposure and the likelihood of elevation of ALT (≥51 IU/L) among adult patients with TB.
  
  
  METHODS
  A retrospective observational study was conducted in patients who underwent periodic monitoring of hepatic function and in whom pharmacokinetic data were collected. Monte Carlo simulation was performed with the intent of identifying the probability of achieving an AUC24 greater than the identified threshold of hepatotoxicity with different dosing regimens (2.5, 5.0 and 7.5 mg/kg/day).
  
  
  RESULTS
  Forty-one out of 185 evaluable patients (22.2%) had an ALT elevation. A mild correlation between isoniazid AUC0-24 and ALT increase was observed (Spearman's ρ = 0.34, P < 0.001). Patients with ALT ≥51 IU/L showed significantly higher isoniazid exposure than those with ALT <51 IU/L (mean AUC24 of 58.33 versus 31.28 mg·h/L, P < 0.001). The probabilities of ALT elevation were 0.82 and 0.12 for isoniazid AUC24 ≥55.0 and <55.0 mg·h/L, respectively. Use of a logistic regression model estimated a likelihood of developing hepatotoxicity of 0.5 and 0.9 when in the presence of an isoniazid AUC24 of 53.7 and 70.0 mg·h/L, respectively. Simulation showed that the standard isoniazid 5 mg/kg daily dose gave a probability of ALT increase of 0.46 for slow acetylators and 0.03 for rapid acetylators.
  
  
  CONCLUSIONS
  Plasma isoniazid exposure might be a valuable predictor of drug-related hepatotoxicity. Early assessment of isoniazid exposure at the beginning of treatment might allow prompt dosage reduction among those patients who are experiencing drug overexposure, thus containing the risk of hepatotoxicity occurrence.
authors.affiliation: Institute of Clinical Pharmacology, Azienda Ospedaliero-Universitaria Santa Maria della Misericordia, Udine, Italy Department of Experimental and Clinical Medical Sciences, University of Udine, Udine, Italy.
authors.forename: Piergiorgio
authors.initials: P
authors.lastname: Cojutti
authors.affiliation: Infectious Diseases Division, Azienda Ospedaliero-Universitaria Santa Maria della Misericordia, Udine, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Duranti
authors.affiliation: Department of Medical and Biological Sciences, Section of Statistics, University of Udine, Udine, Italy.
authors.forename: Miriam
authors.initials: M
authors.lastname: Isola
authors.affiliation: Institute of Clinical Pharmacology, Azienda Ospedaliero-Universitaria Santa Maria della Misericordia, Udine, Italy Department of Experimental and Clinical Medical Sciences, University of Udine, Udine, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Baraldo
authors.affiliation: Infectious Diseases Unit, Department of Medical and Surgical Sciences, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Viale
authors.affiliation: Infectious Diseases Division, Azienda Ospedaliero-Universitaria Santa Maria della Misericordia, Udine, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Bassetti
authors.affiliation: Institute of Clinical Pharmacology, Azienda Ospedaliero-Universitaria Santa Maria della Misericordia, Udine, Italy Department of Experimental and Clinical Medical Sciences, University of Udine, Udine, Italy pea.federico@aoud.sanita.fvg.it.
authors.forename: Federico
authors.initials: F
authors.lastname: Pea
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000410:Alanine Transaminase / Q000097:blood; D000995:Antitubercular Agents / Q000009:adverse effects* / Q000097:blood*; D056486:Chemical and Drug Induced Liver Injury / Q000517:prevention & control*; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D006801:Humans; D007538:Isoniazid / Q000009:adverse effects* / Q000097:blood*; D008297:Male; D008875:Middle Aged; D010949:Plasma / Q000737:chemistry*; D012189:Retrospective Studies; D018570:Risk Assessment; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D000410:Alanine Transaminase; D007538:Isoniazid