Published ahead of print on January 16, 2003, doi:10.1164/rccm.200208-951OC
Am. J. Respir. Crit. Care Med., Volume 167, Number 10, May 2003, 1341-1347
A more recent version of this article appeared on May 15, 2003
Submitted on August 27, 2002
Accepted on January 14, 2003
Low INH Concentrations and Outcome of Tuberculosis Treatment with Once-Weekly INH and Rifapentine
Marc Weiner1*, William Burman2, Andrew Vernon3, Debra Benator4, Charles A Peloquin5, Awal Khan3, Stephen Weis6, Barbara King6, Nina Shah3, Thomas Hodge3, and Tuberculosis Trials Consortium3
1 Medicine, University of Texas Health Science Center San Antonio and South Texas Veterans Health Care System, San Antonio, TX, USA,
2 Denver Public Health and Department of Medicine, University of Colorado Health Science Center, Denver, CO, USA,
3 Division of Tuberculosis Elimination, Centers for Disease Control and Prevention, Atlanta, GA, USA,
4 Medicine, Veterans Administration Medical Center Washington and George Washington University Medical Center, Washington, DC, USA,
5 Pharmacy, National Jewish Medical and Research Center and University of Colorado Schools of of Pharmacy and Medicine, Denver, CO, USA,
6 Medicine, University of North Texas Health Sciences Center, Fort Worth, TX, USA
* To whom correspondence should be addressed. E-mail: weiner{at}uthscsa.edu.
To understand why once-weekly isoniazid/rifapentine therapy for tuberculosis was less effective than twice-weekly isoniazid/rifampin, we studied HIV-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 per week isoniazid/rifapentine (median isoniazid area under the concentration-time curve for 12 hours after the dose [AUC0-12] was 36 µg*h/ml in failure/relapse versus 56 µg*h/ml in controls, P = 0.005), but not with twice weekly isoniazid/rifampin. Further, two patients who relapsed with M. tuberculosis monoresistant to rifamycin had very low concentrations of isoniazid. Finally, isoniazid acetylator status determined by N-acetyltransferase 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.
Key words: tuberculosis, treatment, isoniazid, rifapentine and pharmacokinetics
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