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

Dooley, Kelly E.; Bliven-Sizemore, Erin; Weiner, Marc; Lu, Yanhui; Nuermberger, Eric L.; Hubbard, Walter C.; Fuchs, Edward J.; Melia, Michael T.; Burman, William J.; Dorman, Susan E.

doi:10.1038/clpt.2011.323

Cited by 73 publications

(72 citation statements)

References 32 publications

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“…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). 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).…”

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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

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

101

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“…The FDA-approved rifapentine dose administration for the treatment of tuberculosis, as part of a multidrug regimen, is 600 mg administered twice weekly for the first 2 months of therapy, followed by 600 mg administered once weekly for an additional 4 months (12). However, as part of efforts to optimize drug therapy for tuberculosis, rifapentine daily dosing regimens are also being explored (13,14).…”

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confidence: 99%

Evaluation of the Pharmacokinetic Interaction between Repeated Doses of Rifapentine or Rifampin and a Single Dose of Bedaquiline in Healthy Adult Subjects

Winter

Egizi

Murray

et al. 2015

Antimicrob Agents Chemother

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bThis study assessed the effects of rifapentine or rifampin on the pharmacokinetics of a single dose of bedaquiline and its M2 metabolite in healthy subjects using a two-period single-sequence design. In period 1, subjects received a single dose of bedaquiline (400 mg), followed by a 28-day washout. In period 2, subjects received either rifapentine (600 mg) or rifampin (600 mg) from day 20 to day 41, as well as a single bedaquiline dose (400 mg) on day 29. The pharmacokinetic profiles of bedaquiline and M2 were compared over 336 h after the administration of bedaquiline alone and in combination with steady-state rifapentine or rifampin. Coadministration of bedaquiline with rifapentine or rifampin resulted in lower bedaquiline exposures. The geometric mean ratios (GMRs) and 90% confidence intervals ( B edaquiline (formerly TMC207 and R207910) is a diarylquinoline antitubercular compound that specifically inhibits ATP synthase in Mycobacterium tuberculosis (1). It was approved by the U.S. FDA as part of combination therapy for the treatment of multidrug-resistant pulmonary tuberculosis (TB) on 28 December 2012 (2). The U.S. FDA-approved bedaquiline drug label has a black box highlighting an increased risk of death and QT prolongation (3). In vitro, bedaquiline potently inhibits both drug-sensitive and drug-resistant M. tuberculosis isolates (4, 5) and is also bactericidal against nonreplicating tubercle bacilli (6). In the murine model of tuberculosis, bedaquiline alone showed improved clearance of bacilli over the combination of isoniazid, rifampin, and pyrazinamide, while bedaquiline and pyrazinamide in combination revealed a synergistic interaction that accelerated the clearance of bacilli (7). Since rifampin is currently considered one of the most important so-called sterilizing TB drugs, it was critical to further understand whether a bedaquiline-rifamycin combination should be considered for improved therapeutic efficacy.CYP3A4 is the major cytochrome P450 (CYP450) isoenzyme involved in the metabolism of bedaquiline and the formation of its major N-monodesmethyl metabolite, M2, which is 4 to 6 times less active in terms of antimycobacterial potency. In vitro, bedaquiline does not significantly inhibit the activity of the CYP450 enzymes CYP1A2, CYP2A6, CYP2C8, CYP2D6, CYP2E1, and CYP4A, nor does it induce CYP1A2, or CYP3A4 activities (3). Rifampin and rifapentine are both inducers of a variety of enzymes, including CYP3A4, CYP1A2, CYP2C9, and CYP2D6. Other proteins induced are glucuronyl transferase and p-glycoprotein. The relative ranking of commonly used rifamycins in terms of CYP3A4 enzyme induction potential is rifampin, followed by rifapentine, and finally, rifabutin (8). Given that bedaquiline is metabolized mainly via CYP3A, there is a potential for drug interactions during coadministration of bedaquiline with CYP3A inducers or inhibitors (9). A previous clinical drug interaction study of a single dose of 300 mg of bedaquiline and steady-state 600-mg dosing of rifampin in healthy subjects found that ...

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“…The LC-MS/MS method used for drug quantification was based on previously described methods (15). The analytes of interest were separated using a Waters BEH C8, 50-by 2.1-mm, and 1.7-m particle size column at ambient temperature.…”

Section: Chemicals and Materialsmentioning

confidence: 99%

“…We incorporated DBS collection into a phase I dose escalation trial of RPT (15), with the goal of developing and validating an accurate and reproducible DBS assay to quantify RPT and desRPT, with the desRPT data supporting mathematical model building.…”

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confidence: 99%

Quantification of Rifapentine, a Potent Antituberculosis Drug, from Dried Blood Spot Samples Using Liquid Chromatographic-Tandem Mass Spectrometric Analysis

Parsons

Marzinke

Hoang

et al. 2014

Antimicrob Agents Chemother

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The quantification of antituberculosis drug concentrations in multinational trials currently requires the collection of modest blood volumes, centrifugation, aliquoting of plasma, freezing, and keeping samples frozen during shipping. We prospectively enrolled healthy individuals into the Tuberculosis Trials Consortium Study 29B, a phase I dose escalation study of rifapentine, a rifamycin under evaluation in tuberculosis treatment trials. We developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantifying rifapentine in whole blood on dried blood spots (DBS) to facilitate pharmacokinetic/pharmacodynamic analyses in clinical trials. Paired plasma and whole-blood samples were collected by venipuncture, and whole blood was spotted on Whatman protein saver 903 cards. The methods were optimized for plasma and then validated for DBS. The analytical measuring range for quantification of rifapentine and its metabolite was 50 to 80,000 ng/ml in whole-blood DBS. The analyte was stable on the cards for 11 weeks with a desiccant at room temperature and protected from light. The method concordance for paired plasma and whole-blood DBS samples was determined after correcting for participant hematocrit or population-based estimates of bias from Bland-Altman plots. The application of either correction factor resulted in acceptable correlation between plasma and whole-blood DBS (Passing-Bablok regression corrected for hematocrit; y ‫؍‬ 0.98x ؉ 356). Concentrations of rifapentine may be determined from whole-blood DBS collected via venipuncture after normalization in order to account for the dilutional effects of red blood cells. Additional studies are focused on the application of this methodology to capillary blood collected by finger stick. The simplicity of processing, storage, shipping, and low blood volume makes whole-blood DBS attractive for rifapentine pharmacokinetic evaluations, especially in international and pediatric trials.

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

Cited by 73 publications

References 32 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

Evaluation of the Pharmacokinetic Interaction between Repeated Doses of Rifapentine or Rifampin and a Single Dose of Bedaquiline in Healthy Adult Subjects

Quantification of Rifapentine, a Potent Antituberculosis Drug, from Dried Blood Spot Samples Using Liquid Chromatographic-Tandem Mass Spectrometric Analysis

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