A Phase II Study Of A Rifapentine-Containing Regimen For Intensive Phase Treatment Of Pulmonary Tuberculosis: Preliminary Results For Tuberculosis Trials Consortium Study 29

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

doi:10.1164/ajrccm-conference.2011.183.1_meetingabstracts.a6413

Cited by 8 publications

(14 citation statements)

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“…However, 275 patients in Study 29 received RPT at 10 mg/kg daily with INH, PZA, and EMB for 8 weeks. Safety and tolerability of RPT were not different than for RIF at the same dose (10). In a follow-up study of the safety, tolerability, and PK of escalating doses of RPT in healthy volunteers, drug exposures comparable to P 15 in mice were achieved in human subjects receiving 15 to 20 mg/kg, with food, and were well-tolerated (9).…”

Section: Discussionmentioning

confidence: 88%

“…However, the recently reported results of TB Trials Consortium Study 29 do not support this assumption. In that phase 2 trial, subjects with smearpositive pulmonary TB randomized to receive 10 mg/kg (up to 600 mg) of either RIF or RPT in combination with INH, PZA, and EMB for the first 8 weeks of treatment experienced similar rates of sputum conversion (10), although a trend toward superiority of RPT was observed among subjects with noncavitary disease in a post hoc subgroup analysis. The reason that the benefit of replacing RIF with RPT was not as great in Study 29 as it is in mice is not clear.…”

Section: Discussionmentioning

confidence: 99%

“…A final potential explanation for the apparent discrepancy between murine studies and Study 29 is that the primary end point of phase 2 trials like Study 29, sputum culture conversion at 2 months, may not be an adequate surrogate marker for relapse or the assessment of sterilizing activity (6,10). Only properly designed phase 3 studies based on relapse as the primary outcome can address this issue.…”

Section: Discussionmentioning

confidence: 99%

“…The resistant subpopulation represented less than 1% of the total population in one mouse and less than 0.01% in the other. After 8 weeks of treatment, rifamycin resistance was detected in 3 of 5 C3HeB/FeJ mice receiving R 10 monotherapy, 2 of 5 mice receiving R 20 , and 2 of 5 mice receiving P 10 . With the exception of one R 10 -treated mouse in which the resistant subpopulation represented approximately 0.1% of the total bacillary population, the resistant mutants had overgrown the susceptible population in these mice.…”

Section: Pharmacokinetics Of Rifamycins and Companion Drugs Inmentioning

confidence: 99%

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Dose-Ranging Comparison of Rifampin and Rifapentine in Two Pathologically Distinct Murine Models of Tuberculosis

Rosenthal

Tasneen

Peloquin

et al. 2012

Antimicrob Agents Chemother

146

123

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dIn previous experiments, replacing the 10-mg/kg of body weight daily dose of rifampin with 7.5 to 10 mg/kg of rifapentine in combinations containing isoniazid and pyrazinamide reduced the duration of treatment needed to cure tuberculosis in BALB/c mice by approximately 50% due to rifapentine's more potent activity and greater drug exposures obtained. In the present study, we performed dose-ranging comparisons of the bactericidal and sterilizing activities of rifampin and rifapentine, alone and in combination with isoniazid and pyrazinamide with or without ethambutol, in BALB/c mice and in C3HeB/FeJ mice, which develop necrotic lung granulomas after infection with Mycobacterium tuberculosis. Each rifamycin demonstrated a significant increase in sterilizing activity with increasing dose. Rifapentine was roughly 4 times more potent in both mouse strains. These results reinforce the rationale for ongoing clinical trials to ascertain the highest well-tolerated doses of rifampin and rifapentine. This study also provides an important benchmark for the efficacy of the first-line regimen in C3HeB/FeJ mice, a strain in which the lung lesions observed after M. tuberculosis infection may better represent the pathology of human tuberculosis.T he rifamycins are key sterilizing drugs in the treatment of tuberculosis (TB) (2). Addition of rifampin (RIF, or R) to regimens based on isoniazid (INH, or H) and streptomycin reduced the duration of treatment necessary for cure of human TB from 18 or more months to 9 months, before the subsequent addition of pyrazinamide (PZA, or Z) reduced it to 6 months (3,4,12,13,43). Data from an in vitro hollow fiber model (19), animal models (22,49), and clinical studies (8,23,45) indicate RIF has dose-dependent bactericidal activity that is not optimized at the currently recommended 10-mg/kg of body weight (600 mg maximum) dose for adults (2). It follows that increasing rifamycin exposures may increase bactericidal and sterilizing activities and further shorten the duration of TB treatment (35). To this end, we have previously shown that replacing the 10-mg/kg daily dose of RIF with a 7.5-or 10-mg/kg daily dose of rifapentine (RPT, or P) in combination with INH and PZA reduces the duration of treatment needed to cure TB in mice by approximately 50%, owing to RPT's more potent antituberculosis activity and greater drug exposures obtained at a given dose (in mg/kg) (40, 41). A subsequent dose escalation trial in healthy volunteers showed daily RPT doses as high as 20 mg/kg were well tolerated (9). Daily regimens using RPT doses of 7.5 to 20 mg/kg in place of RIF are now under evaluation for efficacy, safety, and tolerability in at least 3 clinical trials (clinicaltrials.gov identifiers NCT00694629, NCT00728507, and NCT00814671).Unlike RPT, RIF is already in use throughout the world for treatment of TB. Despite 40 years of clinical use, studies to define the highest well-tolerated daily dose are only now under way (clinicaltrials.gov identifiers NCT00760149, NCT01392911, and NCT01408914). To deter...

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Pharmacokinetics Of Rifamycins and Companion Drugs Inmentioning

confidence: 99%

See 2 more Smart Citations

Dose-Ranging Comparison of Rifampin and Rifapentine in Two Pathologically Distinct Murine Models of Tuberculosis

Rosenthal

Tasneen

Peloquin

et al. 2012

Antimicrob Agents Chemother

146

123

View full text Add to dashboard Cite

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“…Recent data in a murine model of active TB showed that increasing rifamycin exposure by daily dosing of P in place of R improved sterilizing activity, suggesting that daily P might permit shortening of treatment duration (28)(29)(30). These encouraging results prompted a large-scale phase 2 clinical trial conducted by the Tuberculosis Trials Consortium (TBTC study 29) to evaluate the safety and efficacy of a regimen in which P is substituted for R during the initial 8 weeks of treatment (13).…”

mentioning

confidence: 99%

Rifapentine Is Not More Active than Rifampin against Chronic Tuberculosis in Guinea Pigs

Dutta

Illei

Peloquin

et al. 2012

Antimicrob Agents Chemother

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e Rifamycins are key sterilizing drugs in the current treatment of active tuberculosis (TB). Daily dosing of rifapentine (P), a potent rifamycin with high intracellular accumulation, in place of rifampin (R) in the standard antitubercular regimen significantly shortens the duration of treatment needed to prevent relapse in a murine model of active TB. We undertook the current study to compare directly the activities of human-equivalent doses of P and R in a guinea pig model of chronic TB, in which bacilli are predominantly extracellular within human-like necrotic granulomas. Hartley strain guinea pigs were aerosol infected with ϳ200 bacilli of Mycobacterium tuberculosis H37Rv, and treatment given 5 days/week was initiated 6 weeks later. R at 100 mg/kg of body weight and P at 100 mg/kg were given orally alone or in combination with isoniazid (H) at 60 mg/kg and pyrazinamide (Z) at 300 mg/kg. Culture-positive relapse was assessed in subgroups of guinea pigs after completion of 1 and 2 months of treatment. Human-equivalent doses of R and P showed equivalent bactericidal activity when used alone and in combination therapy. In guinea pigs treated with rifampin, isoniazid, and pyrazinamide (RHZ) or PHZ, microbiological relapse occurred in the lungs of 8/10 animals treated for 1 month and in 0/10 animals treated for 2 months. Substitution of P for R in the standard antitubercular regimen did not shorten the time to cure in this guinea pig model of chronic TB. Data from ongoing clinical trials comparing the activity of these two drugs are awaited to determine the relevance of the guinea pig TB model in preclinical drug screening. R ifapentine (P), a cyclopentyl rifamycin with a much longer half-life than rifampin (R) (10 to 15 h compared to 2 to 5 h, respectively), was developed with the goal of allowing highly active once-weekly therapy for tuberculosis (TB) (37). However, relative to twice-or thrice-weekly rifampin-isoniazid (RH), once-weekly PH during the continuation phase of treatment was associated with greater drug-susceptible relapse among HIV-negative patients with lung cavitation (8) and a significant incidence of acquired rifamycin monoresistance among HIV-positive patients (35). Recent data in a murine model of active TB showed that increasing rifamycin exposure by daily dosing of P in place of R improved sterilizing activity, suggesting that daily P might permit shortening of treatment duration (28-30). These encouraging results prompted a large-scale phase 2 clinical trial conducted by the Tuberculosis Trials Consortium (TBTC study 29) to evaluate the safety and efficacy of a regimen in which P is substituted for R during the initial 8 weeks of treatment (13).P is known to have significantly higher intracellular accumulation relative to R, as the MIC and minimal bactericidal concentration (MBC) of P against Mycobacterium tuberculosis H37Rv within macrophages are 4-fold lower than the corresponding values against extracellular bacilli (22). On the other hand, the MIC and MBC of R against intracellular M. tu...

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Safety and Pharmacokinetics of Escalating Daily Doses of the Antituberculosis Drug Rifapentine in Healthy Volunteers

Dooley

Bliven-Sizemore

Weiner

et al. 2012

Clin Pharmacol Ther

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Rifapentine (RPT) is an antituberculosis drug that may shorten treatment duration when substituted for rifampin (RIF). The maximal tolerated daily dose of RPT and its potential for cytochrome 3A4 induction and autoinduction at clinically relevant doses are unknown. In this phase I, dose-escalation study among healthy volunteers, daily doses as high as a prespecified maximum of 20 mg/kg/day were well tolerated. Steady-state RPT concentrations increased with dose from 5 to 15 mg/kg, but area under the plasma concentration–time curve (AUC0–24) and maximum concentration (Cmax) were similar in the 15- and 20-mg/kg cohorts. Although RPT pharmacokinetics (PK) appeared to be time-dependent, accumulation occurred with daily dosing. The mean AUC0–12 of oral midazolam (MDZ), a cytochrome 3A (CYP3A) probe drug, was reduced by 93% with the coadministration of RPT and by 74% with the coadministration of RIF (P < 0.01). Changes in the oral clearance of MDZ did not vary by RPT dose. In conclusion, RPT was tolerated at doses as high as 20 mg/kg/day, its PK were less than dose-proportional, and its CYP3A induction was robust.

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A Phase II Study Of A Rifapentine-Containing Regimen For Intensive Phase Treatment Of Pulmonary Tuberculosis: Preliminary Results For Tuberculosis Trials Consortium Study 29

Cited by 8 publications

References 0 publications

Dose-Ranging Comparison of Rifampin and Rifapentine in Two Pathologically Distinct Murine Models of Tuberculosis

Dose-Ranging Comparison of Rifampin and Rifapentine in Two Pathologically Distinct Murine Models of Tuberculosis

Rifapentine Is Not More Active than Rifampin against Chronic Tuberculosis in Guinea Pigs

Safety and Pharmacokinetics of Escalating Daily Doses of the Antituberculosis Drug Rifapentine in Healthy Volunteers

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