Low isoniazid concentrations and outcome of tuberculosis treatment with once-weekly isoniazid and rifapentine

Am J Respir Crit Care Med. 2003 May 15;167(10):1341-7. doi: 10.1164/rccm.200208-951OC. Epub 2003 Jan 16.


To understand why once-weekly isoniazid/rifapentine therapy for tuberculosis was less effective than twice-weekly isoniazid/rifampin, we studied human immunodeficiency virus-seronegative patients with either failure (n = 4), relapse (n = 35), or cure (n = 94), recruited from a comparative treatment trial. In multivariate analyses that were adjusted for severity of disease, low plasma concentrations of isoniazid were associated with failure/relapse with once-weekly isoniazid/rifapentine (median isoniazid area under the concentration-time curve for 12 hours after the dose [AUC(0-12)] was 36 microg x hour/ml in failure/relapse versus 56 microg x hour/ml in control cases p = 0.005), but not with twice-weekly isoniazid/rifampin. Furthermore, two patients who relapsed with Mycobacterium tuberculosis monoresistant to rifamycin had very low concentrations of isoniazid. Finally, isoniazid acetylator status determined by N-acetyltransferase type 2 genotype was associated with outcome with once-weekly isoniazid/rifapentine (p = 0.03) but not twice-weekly isoniazid/rifampin. No rifamycin pharmacokinetic parameter was consistently and significantly associated with outcome (p > 0.10). Because low isoniazid concentrations were associated with failure/relapse, a drug with consistently greater area under the concentration-time curve than isoniazid may be needed to achieve highly active once-weekly therapy with rifapentine.

Publication types

  • Clinical Trial
  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Analysis of Variance
  • Antibiotics, Antitubercular / administration & dosage
  • Antibiotics, Antitubercular / blood
  • Antitubercular Agents / administration & dosage
  • Antitubercular Agents / blood
  • Biological Availability
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Drug Therapy, Combination
  • Female
  • HIV Seronegativity
  • Humans
  • Isoniazid / administration & dosage*
  • Isoniazid / pharmacokinetics*
  • Male
  • Middle Aged
  • Multivariate Analysis
  • Probability
  • Recurrence
  • Reference Values
  • Rifampin / administration & dosage*
  • Rifampin / pharmacokinetics*
  • Severity of Illness Index
  • Treatment Failure
  • Treatment Outcome
  • Tuberculosis, Pulmonary / diagnosis
  • Tuberculosis, Pulmonary / drug therapy*


  • Antibiotics, Antitubercular
  • Antitubercular Agents
  • Isoniazid
  • Rifampin