TY - JOUR
T1 - Low isoniazid concentrations and outcome of tuberculosis treatment with once-weekly isoniazid and rifapentine
AU - Weiner, Marc
AU - Burman, William
AU - Vernon, Andrew
AU - Benator, Debra
AU - Peloquin, Charles A.
AU - Khan, Awal
AU - Weis, Stephen
AU - King, Barbara
AU - Shah, Nina
AU - Hodge, Thomas
PY - 2003/5/15
Y1 - 2003/5/15
N2 - 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 [AUC0-12] was 36 μg·hour/ml in failure/relapse versus 56 μg·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.
AB - 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 [AUC0-12] was 36 μg·hour/ml in failure/relapse versus 56 μg·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.
KW - Isoniazid
KW - Pharmacokinetics
KW - Rifapentine
KW - Treatment
KW - Tuberculosis
UR - http://www.scopus.com/inward/record.url?scp=0037614780&partnerID=8YFLogxK
U2 - 10.1164/rccm.200208-951OC
DO - 10.1164/rccm.200208-951OC
M3 - Article
C2 - 12531776
AN - SCOPUS:0037614780
SN - 1073-449X
VL - 167
SP - 1341
EP - 1347
JO - American Journal of Respiratory and Critical Care Medicine
JF - American Journal of Respiratory and Critical Care Medicine
IS - 10
ER -