Daily rifapentine for treatment of pulmonary tuberculosis: A randomized, dose-ranging trial

Susan E. Dorman

Research output: Contribution to journalArticle

Abstract

Rationale: Rifapentine has potent activity in mouse models of tuberculosis chemotherapy but its optimal dose and exposure in humans are unknown. Objectives: We conducted a randomized, partially blinded dose-ranging study to determine tolerability, safety, and antimicrobial activity of daily rifapentine for pulmonary tuberculosis treatment. Methods: Adults with sputum smear-positive pulmonary tuberculosis were assigned rifapentine 10, 15, or 20 mg/kg or rifampin 10 mg/kg daily for 8 weeks (intensive phase), with isoniazid, pyrazinamide, and ethambutol. The primary tolerability end point was treatment discontinuation. The primary efficacy end point was negative sputum cultures at completion of intensive phase. Measurements and Main Results: Atotal of 334 participants were enrolled. At completion of intensive phase, cultures on solid media were negative in 81.3% of participants in the rifampin group versus 92.5% ( P = 0.097), 89.4% (P = 0.29), and 94.7% (P = 0.049) in the rifapentine 10, 15, and 20 mg/kg groups. Liquid cultures were negative in 56.3% (rifampin group) versus 74.6% ( P = 0.042), 69.7% (P = 0.16), and 82.5% (P = 0.004), respectively. Compared with the rifampin group, the proportion negative at the end of intensive phase was higher among rifapentine recipients who had high rifapentine areas under the concentration-time curve. Percentages of participants discontinuing assigned treatment for reasons other than microbiologic ineligibility were similar across groups (rifampin, 8.2%; rifapentine 10, 15, or 20 mg/kg, 3.4, 2.5, and 7.4%, respectively). Conclusions: Daily rifapentine was well-tolerated and safe. High rifapentine exposures were associated with high levels of sputum sterilization at completion of intensive phase. Further studies are warranted to determine if regimens that deliver high rifapentine exposures can shorten treatment duration to less than 6 months. Clinical trial registered with www.clinicaltrials.gov (NCT 00694629).

Original languageEnglish (US)
Pages (from-to)333-343
Number of pages11
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume191
Issue number3
DOIs
StatePublished - Feb 1 2015

Fingerprint

rifapentine
Pulmonary Tuberculosis
Rifampin
Sputum
Therapeutics
Pyrazinamide
Ethambutol

Keywords

  • Mycobacterium
  • Rifamycins
  • Rifapentine
  • Therapeutics
  • Tuberculosis

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine
  • Medicine(all)

Cite this

Daily rifapentine for treatment of pulmonary tuberculosis : A randomized, dose-ranging trial. / Dorman, Susan E.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 191, No. 3, 01.02.2015, p. 333-343.

Research output: Contribution to journalArticle

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abstract = "Rationale: Rifapentine has potent activity in mouse models of tuberculosis chemotherapy but its optimal dose and exposure in humans are unknown. Objectives: We conducted a randomized, partially blinded dose-ranging study to determine tolerability, safety, and antimicrobial activity of daily rifapentine for pulmonary tuberculosis treatment. Methods: Adults with sputum smear-positive pulmonary tuberculosis were assigned rifapentine 10, 15, or 20 mg/kg or rifampin 10 mg/kg daily for 8 weeks (intensive phase), with isoniazid, pyrazinamide, and ethambutol. The primary tolerability end point was treatment discontinuation. The primary efficacy end point was negative sputum cultures at completion of intensive phase. Measurements and Main Results: Atotal of 334 participants were enrolled. At completion of intensive phase, cultures on solid media were negative in 81.3{\%} of participants in the rifampin group versus 92.5{\%} ( P = 0.097), 89.4{\%} (P = 0.29), and 94.7{\%} (P = 0.049) in the rifapentine 10, 15, and 20 mg/kg groups. Liquid cultures were negative in 56.3{\%} (rifampin group) versus 74.6{\%} ( P = 0.042), 69.7{\%} (P = 0.16), and 82.5{\%} (P = 0.004), respectively. Compared with the rifampin group, the proportion negative at the end of intensive phase was higher among rifapentine recipients who had high rifapentine areas under the concentration-time curve. Percentages of participants discontinuing assigned treatment for reasons other than microbiologic ineligibility were similar across groups (rifampin, 8.2{\%}; rifapentine 10, 15, or 20 mg/kg, 3.4, 2.5, and 7.4{\%}, respectively). Conclusions: Daily rifapentine was well-tolerated and safe. High rifapentine exposures were associated with high levels of sputum sterilization at completion of intensive phase. Further studies are warranted to determine if regimens that deliver high rifapentine exposures can shorten treatment duration to less than 6 months. Clinical trial registered with www.clinicaltrials.gov (NCT 00694629).",
keywords = "Mycobacterium, Rifamycins, Rifapentine, Therapeutics, Tuberculosis",
author = "Dorman, {Susan E.} and Dorman, {Susan E.} and Savic, {Radojka M.} and Stefan Goldberg and Stout, {Jason E.} and Neil Schluger and Grace Muzanyi and Johnson, {John L.} and Payam Nahid and Hecker, {Emily J.} and Heilig, {Charles M.} and Lorna Bozeman and Feng, {Pei Jean I} and Moro, {Ruth N.} and William MacKenzie and Dooley, {Kelly E.} and Nuermberger, {Eric L.} and Andrew Vernon and Marc Weiner",
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AU - Goldberg, Stefan

AU - Stout, Jason E.

AU - Schluger, Neil

AU - Muzanyi, Grace

AU - Johnson, John L.

AU - Nahid, Payam

AU - Hecker, Emily J.

AU - Heilig, Charles M.

AU - Bozeman, Lorna

AU - Feng, Pei Jean I

AU - Moro, Ruth N.

AU - MacKenzie, William

AU - Dooley, Kelly E.

AU - Nuermberger, Eric L.

AU - Vernon, Andrew

AU - Weiner, Marc

PY - 2015/2/1

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N2 - Rationale: Rifapentine has potent activity in mouse models of tuberculosis chemotherapy but its optimal dose and exposure in humans are unknown. Objectives: We conducted a randomized, partially blinded dose-ranging study to determine tolerability, safety, and antimicrobial activity of daily rifapentine for pulmonary tuberculosis treatment. Methods: Adults with sputum smear-positive pulmonary tuberculosis were assigned rifapentine 10, 15, or 20 mg/kg or rifampin 10 mg/kg daily for 8 weeks (intensive phase), with isoniazid, pyrazinamide, and ethambutol. The primary tolerability end point was treatment discontinuation. The primary efficacy end point was negative sputum cultures at completion of intensive phase. Measurements and Main Results: Atotal of 334 participants were enrolled. At completion of intensive phase, cultures on solid media were negative in 81.3% of participants in the rifampin group versus 92.5% ( P = 0.097), 89.4% (P = 0.29), and 94.7% (P = 0.049) in the rifapentine 10, 15, and 20 mg/kg groups. Liquid cultures were negative in 56.3% (rifampin group) versus 74.6% ( P = 0.042), 69.7% (P = 0.16), and 82.5% (P = 0.004), respectively. Compared with the rifampin group, the proportion negative at the end of intensive phase was higher among rifapentine recipients who had high rifapentine areas under the concentration-time curve. Percentages of participants discontinuing assigned treatment for reasons other than microbiologic ineligibility were similar across groups (rifampin, 8.2%; rifapentine 10, 15, or 20 mg/kg, 3.4, 2.5, and 7.4%, respectively). Conclusions: Daily rifapentine was well-tolerated and safe. High rifapentine exposures were associated with high levels of sputum sterilization at completion of intensive phase. Further studies are warranted to determine if regimens that deliver high rifapentine exposures can shorten treatment duration to less than 6 months. Clinical trial registered with www.clinicaltrials.gov (NCT 00694629).

AB - Rationale: Rifapentine has potent activity in mouse models of tuberculosis chemotherapy but its optimal dose and exposure in humans are unknown. Objectives: We conducted a randomized, partially blinded dose-ranging study to determine tolerability, safety, and antimicrobial activity of daily rifapentine for pulmonary tuberculosis treatment. Methods: Adults with sputum smear-positive pulmonary tuberculosis were assigned rifapentine 10, 15, or 20 mg/kg or rifampin 10 mg/kg daily for 8 weeks (intensive phase), with isoniazid, pyrazinamide, and ethambutol. The primary tolerability end point was treatment discontinuation. The primary efficacy end point was negative sputum cultures at completion of intensive phase. Measurements and Main Results: Atotal of 334 participants were enrolled. At completion of intensive phase, cultures on solid media were negative in 81.3% of participants in the rifampin group versus 92.5% ( P = 0.097), 89.4% (P = 0.29), and 94.7% (P = 0.049) in the rifapentine 10, 15, and 20 mg/kg groups. Liquid cultures were negative in 56.3% (rifampin group) versus 74.6% ( P = 0.042), 69.7% (P = 0.16), and 82.5% (P = 0.004), respectively. Compared with the rifampin group, the proportion negative at the end of intensive phase was higher among rifapentine recipients who had high rifapentine areas under the concentration-time curve. Percentages of participants discontinuing assigned treatment for reasons other than microbiologic ineligibility were similar across groups (rifampin, 8.2%; rifapentine 10, 15, or 20 mg/kg, 3.4, 2.5, and 7.4%, respectively). Conclusions: Daily rifapentine was well-tolerated and safe. High rifapentine exposures were associated with high levels of sputum sterilization at completion of intensive phase. Further studies are warranted to determine if regimens that deliver high rifapentine exposures can shorten treatment duration to less than 6 months. Clinical trial registered with www.clinicaltrials.gov (NCT 00694629).

KW - Mycobacterium

KW - Rifamycins

KW - Rifapentine

KW - Therapeutics

KW - Tuberculosis

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