Pharmacokinetics-Pharmacodynamics of Rifampin in an Aerosol Infection Model of Tuberculosis

Jayaram, Ramesh; Gaonkar, Sheshagiri; Kaur, Parvinder; Suresh, B. L.; Mahesh, B. N.; Jayashree, R.; Nandi, Vrinda; Bharat, Sowmya; Shandil, Radha; Ethirajulu, Kantharaj; Balasubramanian, V.

doi:10.1128/aac.47.7.2118-2124.2003

Cited by 325 publications

(337 citation statements)

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“…Studies in the murine model have demonstrated that increasing the dose of P from 10 to 15 mg/kg increases the anti-TB activity (16), a finding consistent with the concentration-dependent activity of the rifamycins (17)(18)(19). Once-weekly continuation phase regimens based on a 15-mg/kg dose of P are at least as active as twice-weekly RH, but are not as active as daily RH (9).…”

mentioning

confidence: 57%

Potent Twice-Weekly Rifapentine-containing Regimens in Murine Tuberculosis

Rosenthal

Williams²,

Tyagi³

et al. 2006

Am J Respir Crit Care Med

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Rationale: Recent studies have demonstrated that intermittent administration of rifamycin-based regimens results in higher rates of tuberculosis relapse and treatment failure compared with daily therapy. Twice-weekly treatment with rifampin, isoniazid, and pyrazinamide may be improved by increasing Mycobacterium tuberculosis exposure to rifamycin by substituting rifapentine for rifampin. Methods: To test this hypothesis, we compared the activities of standard daily and twice-weekly rifampin plus isoniazid-based regimens to those of twice-weekly rifapentine plus isoniazid-or moxifloxacin-containing regimens in the murine model of tuberculosis. Relapse rates were assessed after 4, 5, and 6 mo of treatment to assess stable cure. Single-and multiple-dose pharmacokinetics of rifampin and rifapentine were also determined. Results: After 2 mo of treatment, twice-weekly therapy with rifapentine (15 or 20 mg/kg), moxifloxacin, and pyrazinamide was significantly more active than standard daily or twice-weekly therapy with rifampin, isoniazid, and pyrazinamide. Stable cure was achieved after 4 mo of twice-weekly rifapentine plus isoniazid-or moxifloxacincontaining therapy, but only after 6 mo of standard daily therapy. Twice-weekly rifapentine (15 mg/kg) displayed more favorable pharmacodynamics than did daily rifampin (10 mg/kg). In the treatment of drug-susceptible pulmonary tuberculosis (TB), daily administration of a standardized 6-mo regimen including rifampin (R), isoniazid (H), and pyrazinamide (Z; collectively, RHZ) is highly effective in achieving cure (1). But, because supervision of daily treatment imposes a substantial burden on both patients and treatment programs (2, 3), intermittent regimens with predominantly twice-or thrice-weekly drug administration are recommended for supervised therapy (4, 5). Although at least one randomized clinical trial has shown that daily and thrice-weekly RHZ-based regimens have similar efficacy, more recent observational studies suggest intermittent therapy is not as effective as daily therapy, particularly in patients at high risk for relapse (6-8). Recent experience in the murine model of TB supports the latter observations. Daily administration of the 6-mo RHZ-based regimen is significantly more effective than the same regimen administered according to a predominantly twice-weekly schedule (9).The rifamycins are the key drugs in modern short-course therapy. Rifapentine (P) is a rifamycin with a lower minimum inhibitory concentration (MIC) against Mycobacterium tuberculosis and a much longer serum half-life compared with R (10). While P is approved for twice-weekly administration at a dose of 10 mg/kg during the initial phase of therapy (11), several influential clinical trials have focused attention on the use of once-weekly administration of P in combination with H during the continuation phase. In Tuberculosis Trials Consortium Study 22, once-weekly PH was less effective than twice-weekly RH, and was associated with rifamycin-resistant relapse among HIVinfected patients (12...

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mentioning

confidence: 57%

Potent Twice-Weekly Rifapentine-containing Regimens in Murine Tuberculosis

Rosenthal

Williams²,

Tyagi³

et al. 2006

Am J Respir Crit Care Med

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“…Rifamycins have durable sterilizing activity against Mycobacterium tuberculosis, and the currently recommended 10 mg/kg dosage of rifampin, the most commonly used rifamycin, is at the low end of the dose-response curve (2)(3)(4)(5)(6)(7)(8)(9). Historically, selection of this rifampin dose seems to have been influenced by cost in the setting of incomplete dose-finding studies (10).…”

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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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“…During this time, progress has also been made in the quantitative description of both pharmacokinetics (PK) and in vitro pharmacodynamics (PD) of antituberculosis drugs [17], [18], [19]. Mathematical models that arise from a systems approach offer a unique potential to establish quantitative links across multiple biological scales.…”

Section: Tuberculosis Modellingmentioning

confidence: 99%

Systems Medicine and Infection

Bowness

2016

Methods in Molecular Biology

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SummaryBy using a systems based approach, mathematical and computational techniques can be used to develop models that describe the important mechanisms involved in infectious diseases. An iterative approach to model development allows new discoveries to continually improve the model, and ultimately increase the accuracy of predictions.SIR models are used to describe epidemics, predicting the extent and spread of disease.Genome-wide genotyping and sequencing technologies can be used to identify the biological mechanisms behind diseases. These tools help to build strategies for disease prevention and treatment, an example being the recent outbreak of Ebola in West Africa where these techniques were deployed.HIV is a complex disease where much is still to be learnt about the virus and the best effective treatment. With basic mathematical modelling techniques, significant discoveries have been made over the last 20 years. With recent technological advances, the computational resources now available and interdisciplinary cooperation, further breakthroughs are inevitable.In TB, modelling has traditionally been empirical in nature, with clinical data providing the fuel for this top-down approach. Recently, projects have begun to use data derived from laboratory experiments and clinical trials to create mathematical models that describe the mechanisms responsible for the disease.A systems medicine approach to infection modelling helps identify important biological questions that then direct future experiments, the results of which improve the model in an iterative cycle. This means that data from several model systems can be integrated and synthesised to explore complex biological systems.

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Pharmacokinetics-Pharmacodynamics of Rifampin in an Aerosol Infection Model of Tuberculosis

Cited by 325 publications

References 30 publications

Potent Twice-Weekly Rifapentine-containing Regimens in Murine Tuberculosis

Potent Twice-Weekly Rifapentine-containing Regimens in Murine Tuberculosis

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

Systems Medicine and Infection

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