Substitution of Rifapentine for Rifampin During Intensive Phase Treatment of Pulmonary Tuberculosis: Study 29 of the Tuberculosis Trials Consortium

Dorman, Susan E.; Goldberg, Stefan; Stout, Jason E.; Muzanyi, Grace; Johnson, John L.; Weiner, Marc; Bozeman, Lorna; Heilig, Charles M.; Feng, Pei Jean I; Moro, Ruth N.; Narita, Michiko; Nahid, Payam; Ray, Susan M.; Bates, Edward H.; Haile, Betial; Nuermberger, Eric L.; Vernon, Andrew; Schluger, Neil W.

doi:10.1093/infdis/jis461

Cited by 100 publications

(97 citation statements)

References 25 publications

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“…Most strikingly, antimicrobial activity was strongly associated with rifapentine exposure. Among participants with higher rifapentine exposures (AUC >324 mg*h/ml), 80-90% had negative cultures on liquid media at the completion of intensive phase, compared with 56% in the control group in this study and 54-65% in control groups in other recent phase 2 trials conducted by our consortium in similar populations (20,30). Is the antimycobacterial activity observed with the higher rifapentine exposures sufficient to achieve durable cure in less than 6 months and thereby shorten the duration of treatment for drugsusceptible pulmonary TB?…”

Section: Discussioncontrasting

confidence: 43%

“…A phase 1 clinical trial showed that rifapentine doses up to 20 mg/kg administered daily were well-tolerated and safe in healthy volunteers (19). A previous phase 2 clinical trial found 10 mg/kg of daily rifapentine to be as safe as, but not more efficacious than, 10 mg/kg of daily rifampin during the first 8 weeks of combination TB chemotherapy (20). We conducted a dose-ranging clinical trial to determine the optimal dose of daily rifapentine during the first 8 weeks (intensive phase) of combination treatment for pulmonary TB.…”

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confidence: 99%

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Daily Rifapentine for Treatment of Pulmonary Tuberculosis. A Randomized, Dose-Ranging Trial

Dorman

Savic

Goldberg

et al. 2015

Am J Respir Crit Care Med

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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:A total 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).

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Section: Discussioncontrasting

confidence: 43%

mentioning

confidence: 99%

Daily Rifapentine for Treatment of Pulmonary Tuberculosis. A Randomized, Dose-Ranging Trial

Dorman

Savic

Goldberg

et al. 2015

Am J Respir Crit Care Med

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“…To date, however, murine models have provided an accurate representation of the contribution of Z to existing TB regimens (24) and the comparative EBA of H, M, and L (3,9,20). However, results in this model have not always been confirmed in clinical trials using sputum culture conversion as a surrogate endpoint (17,54) for cure. Second, it may be argued that the more rapid clearance of the fluoroquinolones in mice than in humans results in different serum pharmacokinetic profiles that make extrapolation of the results to humans difficult.…”

Section: Discussionmentioning

confidence: 99%

Contribution of Moxifloxacin or Levofloxacin in Second-Line Regimens with or without Continuation of Pyrazinamide in Murine Tuberculosis

Ahmad

Tyagi

Minkowski

et al. 2013

Am J Respir Crit Care Med

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Rationale: High-dose levofloxacin (L) (1,000 mg) was as active as moxifloxacin (M) (400 mg) in an early bactericidal activity trial, suggesting these fluoroquinolones could be used interchangeably. Whether pyrazinamide (Z) contributes sterilizing activity beyond the first 2 months in fluoroquinolone-containing second-line regimens remains unknown. Objectives: We compared the efficacy of M and high-dose L alone or in combination with ethionamide (Et), amikacin (A), and Z given for 2 or 7 months. Methods: A pharmacokinetic study was performed to determine the L dose equivalent to 1,000 mg in humans. Treatment started 2 weeks after aerosol infection with Mycobacterium tuberculosis H37Rv. Mice received M or L alone or in combination with 2 months of EtZA followed by 5 months of Et or EtZ. Measurements and Main Results: After 2 months of treatment, lung colony-forming unit (CFU) counts were similar in mice receiving either fluoroquinolone alone, but, after 4 and 5 months, CFU counts were 2 log 10 lower in mice receiving M. Mice receiving 2MEtZA/3MEt and 2LEtZA/3LEt had 1.0 and 2.7 log 10 lung CFUs, respectively. When Z was given throughout, both regimens rendered mice culture negative by 5 months, and most mice did not relapse after 7 months of treatment, with fewer relapses observed in the M group after 6 and 7 months of treatment. Conclusions: In murine tuberculosis, M had superior efficacy compared with L despite lower serum drug exposures and may remain the fluoroquinolone of choice for second-line regimens. Z contributed substantial sterilizing activity beyond 2 months in fluoroquinolonecontaining second-line regimens, largely compensating for L's weaker activity.

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“…383 A key lesson that has been learned is that defining optimal drug doses is a necessary step in optimising regimen efficacy and preventing the emergence of resistance. [384][385][386][387] Astonishingly, 50 years has passed since the introduction of rifampicin into clinical use, and the optimal dose of this key sterilising drug has yet to be established. Some data suggest that dose optimisation of rifampicin or rifapentine alone might deliver a 4-month regimen that is less likely to select for isoniazid-resistant and MDR disease than the 6-month regimen.…”

Section: Constructing Regimens: Tools and Strategiesmentioning

confidence: 99%

“…Some data suggest that dose optimisation of rifampicin or rifapentine alone might deliver a 4-month regimen that is less likely to select for isoniazid-resistant and MDR disease than the 6-month regimen. [384][385][386][387] Repetition of the mistake of underdosing with new drugs should be avoided in drug-resistant tuberculosis regimens, because resistance could rapidly emerge. For repurposed drugs, doses used to treat other infections should not be assumed to be optimal for drug-resistant tuberculosis treatment, in which disease-specific pharmacokineticpharmacodynamic associations, longer treatment durations, overlapping toxicities, and drug-drug interactions associated with combin ation therapy are important factors in establishing optimal doses.…”

Section: Constructing Regimens: Tools and Strategiesmentioning

confidence: 99%

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

Dheda

Gumbo

Maartens

et al. 2017

The Lancet Respiratory Medicine

506

474

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Substitution of Rifapentine for Rifampin During Intensive Phase Treatment of Pulmonary Tuberculosis: Study 29 of the Tuberculosis Trials Consortium

Abstract: NCT00694629.

Cited by 100 publications

References 25 publications

Daily Rifapentine for Treatment of Pulmonary Tuberculosis. A Randomized, Dose-Ranging Trial

Daily Rifapentine for Treatment of Pulmonary Tuberculosis. A Randomized, Dose-Ranging Trial

Contribution of Moxifloxacin or Levofloxacin in Second-Line Regimens with or without Continuation of Pyrazinamide in Murine Tuberculosis

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

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