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

Rosenthal, Ian M.; Tasneen, Rokeya; Peloquin, Charles A.; Zhang, Ming; Almeida, Deepak; Mdluli, Khisimuzi; Karakousis, Petros C.; Grosset, J; Nuermberger, Eric L.

doi:10.1128/aac.00912-12

Cited by 146 publications

(142 citation statements)

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“…Compared with rifampin, rifapentine has a longer half-life and lower minimum inhibitory concentration against M. tuberculosis (11)(12)(13)(14)(15). Preclinical studies using mouse models have shown that regimens containing daily rifapentine can cure TB after only 3 months of treatment (16)(17)(18). 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).…”

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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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101

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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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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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101

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“…Clinical trial simulations demonstrate that splitting the dose or taking the dose with food could substantially increase daily RFP exposures, which is a significant finding, given that RFP's activity appears to correlate best with AUC/MIC and that current dosing achieves concentrations that are still on the steep part of the dose-response curve. The dose-response relationship was reported in mouse studies (20), guinea pig studies (21), and patient early bactericidal activity studies (22). Most importantly, preliminary results from the recently completed phase IIb TBTC trial 29X in patients suggests a pronounced exposure-response relationship, where the time to culture conversion on solid and liquid media was best predicted by rifapentine exposure (23).…”

Section: Figmentioning

confidence: 96%

Population Pharmacokinetics of Rifapentine and Desacetyl Rifapentine in Healthy Volunteers: Nonlinearities in Clearance and Bioavailability

Savic

Bliven-Sizemore

et al. 2014

Antimicrob Agents Chemother

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Rifapentine is under active investigation as a potent drug that may help shorten the tuberculosis (TB) treatment duration. A previous rifapentine dose escalation study with daily dosing indicated a possible decrease in bioavailability as the dose increased and an increase in clearance over time for rifapentine and its active metabolite, desacetyl rifapentine. This study aimed to assess the effects of increasing doses on rifapentine absorption and bioavailability and to evaluate the clearance changes over 14 days. A population analysis was performed with nonlinear mixed-effects modeling. Absorption, time-varying clearance, bioavailability, and empirical and semimechanistic autoinduction models were investigated. A one-compartment model linked to a transit compartment absorption model best described the data. The bioavailability of rifapentine decreased linearly by 2.5% for each 100-mg increase in dose. The autoinduction model suggested a dose-independent linear increase in clearance of the parent drug and metabolite over time from 1.2 and 3.1 liters · h ؊1 , respectively, after a single dose to 2.2 and 5.0 liters · h ؊1 , respectively, after 14 once-daily doses, with no plateau being reached by day 14. In clinical trial simulations using the final model, rifapentine demonstrated less-than-dose-proportional pharmacokinetics, but there was no plateau in exposures over the dose range tested (450 to 1,800 mg), and divided dosing increased exposures significantly. Thus, the proposed compartmental model incorporating daily dosing of rifapentine over a wide range of doses and time-related changes in bioavailability and clearance provides a useful tool for estimation of drug exposure that can be used to optimize rifapentine dosing for TB treatment. (This study has been registered at ClinicalTrials.gov under registration no. NCT01162486.) T uberculosis (TB) is a major global health problem and remains a leading cause of death from an infectious disease (1). The current first-line regimen for TB was developed decades ago, and 6 months of treatment is still required for cure (2). The long duration is challenging for patients and costly to TB programs. Rifapentine (RFP) is a cyclopentyl analogue of rifampin, the key sterilizing agent in the standard TB treatment regimen that kills bacteria by inhibiting DNA-dependent RNA polymerase. RFP has higher antimicrobial potency and a longer half-life than rifampin and was approved by the Food and Drug Administration (FDA) for treatment of TB at a dose of 600 mg twice weekly (in the intensive phase) and once weekly (in the continuation phase) (3). However, the relapse rate among patients in some patient populations treated with such an intermittent RFP regimen is unacceptably high, indicating that the optimal dosing regimen of RFP for TB treatment has yet to be fully characterized. Recent studies in a well-validated mouse model of TB disease have shown that the replacement of rifampin with RFP can shorten the treatment duration to 3 months or less when RFP is given daily and that RFP'...

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“…Mycobacterium tuberculosis strain H37Rv was used as a frozen stock prepared from a log-phase culture in Middlebrook 7H9 broth after mouse passage, and it was diluted in 7H9 broth before infection (12).…”

Section: Methodsmentioning

confidence: 99%

Sterilizing Activity of Pyrazinamide in Combination with First-Line Drugs in a C3HeB/FeJ Mouse Model of Tuberculosis

Lanoix

Betoudji

Nuermberger

2016

Antimicrob Agents Chemother

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c Pyrazinamide (PZA) is a key sterilizing drug in first-line tuberculosis (TB) regimens and exerts its activity entirely during the first 2 months in human infections. We recently described the reduced activity of PZA in C3HeB/FeJ mice with large caseous tubercles due to neutral pH. Here, we aimed to determine the contribution of PZA to the sterilizing activity of the first-line TB regimen in C3HeB/FeJ and BALB/c mice. Three regimens were compared (in combinations: R, rifampin; H, isoniazid; E, ethambutol; Z, pyrazinamide; with numbers indicating the treatment duration, in months): 2RHEZ/4RH, 2RHE/4RH, and 2RHEZ/4RHZ. Lung CFU counts were assessed after 0 and 2 months of treatment, and relapse rates were assessed 3 months after 3, 4.5, and 6 months of treatment. The relapse rates after 3 months of treatment were 53% and 95% in C3HeB/FeJ mice receiving 2RHEZ/1RH and 2RHE/1RH, respectively, and 67%, 100%, and 80% in BALB/c receiving 2RHEZ/1RH, 2RHE/1RH, and 2RHEZ/1RHZ, respectively. The relapse rates after 4.5 months of treatment were 32%, 20%, and 0% in C3HeB/FeJ mice receiving 2RHEZ/2.5RH, 2RHE/2.5RH, and 2RHEZ/2.5RHZ, respectively, and 0% and 67% in BALB/c receiving 2RHEZ/2.5RH and 2RHE/2.5RH, respectively. The month-6 relapse rates were 0%, 13%, and 0% in C3HeB/FeJ mice given 2RHEZ/4RH, 2RHE/4RH, and 2RHEZ/4RHZ, respectively, and 7% in BALB/c mice receiving 2RHE/4RH. The addition of PZA shortens the duration of treatment needed to prevent relapse in both mouse strains. However, while its contribution is limited to the first 2 months of treatment in BALB/c mice, continuing PZA beyond the first 2 months is beneficial in C3HeB/FeJ mice by preventing relapse among those with the highest disease burden. P yrazinamide (PZA, Z in combinations) has a unique and important role in the first-line regimen used to treat tuberculosis (TB). Whether administered alone or in combination with other first-line drugs, PZA has little or no effect on viable bacterial counts in sputum over the first 2 weeks of treatment. However, when it is absent from the regimen, the subjects are significantly less likely to have their sputum cultures sterilized by 2 months of treatment (1), and the recommended treatment duration is routinely extended from 6 to 9 months in order to achieve comparable rates of cure without relapse (2). Interestingly, PZA contributes this treatment-shortening, or sterilizing, effect within the first 2 months of treatment (3). Indeed, when PZA was administered in combination with rifampin (RIF, R in combinations), isoniazid (INH, H in combinations), and streptomycin (STR, S in combinations), no difference in relapse was observed between the arms treated with PZA for 2 months (2RHSZ/RH) and the arms treated with PZA for up to 6 months (2RHSZ/RHZ) (3). The limited activity of PZA in the continuation phase of treatment has also been demonstrated in murine models of TB (4, 5). This unique time-limited contribution of PZA in the first-line regimen is attributed to its pH-dependent activity, which is diminished with time w...

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

Cited by 146 publications

References 41 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

Population Pharmacokinetics of Rifapentine and Desacetyl Rifapentine in Healthy Volunteers: Nonlinearities in Clearance and Bioavailability

Sterilizing Activity of Pyrazinamide in Combination with First-Line Drugs in a C3HeB/FeJ Mouse Model of Tuberculosis

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