title: Low isoniazid concentrations and outcome of tuberculosis treatment with once-weekly isoniazid and rifapentine.
abstract: 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.
authors.affiliation: University of Texas Health Science Center, South Texas Veterans Health Care System, San Antonio 78284, USA. weiner@uthscsa.edu
authors.forename: Marc
authors.initials: M
authors.lastname: Weiner
authors.forename: William
authors.initials: W
authors.lastname: Burman
authors.forename: Andrew
authors.initials: A
authors.lastname: Vernon
authors.forename: Debra
authors.initials: D
authors.lastname: Benator
authors.forename: Charles A
authors.initials: CA
authors.lastname: Peloquin
authors.forename: Awal
authors.initials: A
authors.lastname: Khan
authors.forename: Stephen
authors.initials: S
authors.lastname: Weis
authors.forename: Barbara
authors.initials: B
authors.lastname: King
authors.forename: Nina
authors.initials: N
authors.lastname: Shah
authors.forename: Thomas
authors.initials: T
authors.lastname: Hodge
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D000904:Antibiotics, Antitubercular / Q000008:administration & dosage / Q000097:blood; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000097:blood; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D018023:HIV Seronegativity; D006801:Humans; D007538:Isoniazid / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011336:Probability; D012008:Recurrence; D012016:Reference Values; D012293:Rifampin / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D012720:Severity of Illness Index; D017211:Treatment Failure; D016896:Treatment Outcome; D014397:Tuberculosis, Pulmonary / Q000175:diagnosis / Q000188:drug therapy*
chemical_list: D000904:Antibiotics, Antitubercular; D000995:Antitubercular Agents; D007538:Isoniazid; D012293:Rifampin