© 2004 American Thoracic Society
Rifapentine for the Treatment of TuberculosisIs It All It Can Be?Veterans Affairs Medical Center and The George Washington University Washington, D.C. Simplification of treatment regimens for tuberculosis is an urgent research priority to control global tuberculosis (1). Currently, most patients with tuberculosis require 6 months of treatment with drugs given twice weekly. There are two possible simplifications: shorten the duration of treatment, or devise regimens that can be delivered less often. The development of rifapentine as a long-acting rifamycin gave hope that tuberculosis could be successfully treated with a once-weekly regimen. This hope has yet to be fully realized, however, as studies of once-weekly regimens containing 600 mg of rifapentine have been found to be somewhat inferior to twice-weekly rifampin-containing regimens for persons with cavitary and advanced tuberculosis (2, 3). In this issue of the Journal (pp. 1191–1197), Weiner and colleagues provide pharmacokinetic data from a pilot study of 900 and 1,200 mg of rifapentine in the treatment of tuberculosis (4). These data raise interesting issues about whether clinical trials to date have used the optimum dose of this drug and, therefore, whether the past results represent the best that can be achieved with rifapentine. The development of new drugs for tuberculosis is a slow and difficult process. Despite the fact that, worldwide, there are 8 million cases and 3 million deaths annually from tuberculosis, there has been little interest in new drug development from the pharmaceutical industry. When rifapentine was approved for tuberculosis in 1998 by the Food and Drug Administration, it represented the first new drug approved for this indication in over 30 years. It is therefore critical to maximize the benefit from those drugs which do exist. Rifapentine has a potential advantage over rifampin because its long half-life (13 hours compared with 3 hours) could allow for less frequent dosing. Trials have investigated using rifapentine at a dose of 600 mg once weekly in combination with isoniazid in the continuation phase of tuberculosis treatment (2, 3). As Weiner and colleagues note, however, due to unacceptable failure rates in persons with advanced tuberculosis, the current national treatment recommendations limit the use of weekly rifapentine and isoniazid to populations with less severe disease (1). In an effort to improve upon the results achieved with rifapentine, a study was undertaken to examine the tolerability and pharmacokinetics of using higher doses of rifapentine for treatment of tuberculosis. The Tuberculosis Trials Consortium (TBTC), under the sponsorship of the Centers for Disease Control and Prevention, evaluated rifapentine at doses of 600, 900, and 1,200 mg given once weekly with 900 mg of isoniazid in the continuation phase of tuberculosis treatment (5). With just 150 patients (50 in each of the 3 dose arms), the study was only able to evaluate safety and tolerability of the two higher doses—but not efficacy. Weiner and colleagues evaluated rifapentine serum levels in a subset of 35 of these 150 patients. Both the mean rifapentine maximum serum concentration and the mean area under the curve increased as the dose increased from 600 to 900 to 1,200 mg. The half-life of rifapentine was similar for all 3 doses and, by 72 hours, serum levels were negligible. As the authors note, the clinical significance of these higher drug levels is unclear. It is not known if peak serum concentration is a critical factor in the ability of rifapentine to kill Mycobacterium tuberculosis. For rifampin, early studies did demonstrate a clear dose-dependant effect on clinical outcome (6), but no similar studies have been done with rifapentine in humans. To simulate such an effect, Weiner and colleagues have constructed a diagram (Figure 3 of their article) comparing the achieved serum levels of 600, 900, and 1,200 mg of rifapentine to the minimum inhibitory concentration for M. tuberculosis. Using their diagram, all three doses appear to have adequate antimycobacterial activity at 12 and 24 hours, although there may be a slight advantage to the 1200 mg dose, with continued activity out to 48 hours. What, then, should be drawn from these intriguing data? Have we used too low a dose of rifapentine in the trials done to date—and not taken full advantage of this drug? The answer is not clear. One of the major concerns in the rifapentine trials has been the lack of a companion drug able to take advantage of the long half-life of rifapentine. The failure of the studies of rifapentine and isoniazid in treating patients with extensive disease may have more to do with isoniazid than rifapentine. This has been shown in a study from the Tuberculosis Trials Consortium: in patients receiving 600 mg of rifapentine and 900 mg isoniazid once weekly, low levels of isoniazid were associated with clinical failure and relapse (7). If one were to increase the dose of rifapentine to 900 or 1,200 mg, the high serum levels demonstrated by Weiner and colleagues might, in fact, result in more exposure to the rifamycin alone, perhaps increasing the likelihood of rifampin-resistant tuberculosis in persons who fail therapy or relapse (7, 8). The solution to this problem would be to combine rifapentine with another antituberculosis drug with a long half-life. One drug worthy of consideration is moxifloxacin, a drug with a half-life of 12 hours and excellent in vitro efficacy against M. tuberculosis. The combination of rifapentine and moxifloxacin has already proven to have clinical benefit in a well established murine model of tuberculosis (9). The data of Weiner and colleagues (4) on higher levels of rifapentine do have immediate impact in the evaluation of this drug for the treatment of latent tuberculosis infection: in latent tuberculosis, the low burden of mycobacteria and the slow metabolic state are such that single drug therapy is routinely used without concern about the development of drug resistance (10). In this situation, higher drug levels would be a benefit. Based on this assumption, the Tuberculosis Trials Consortium is currently enrolling 8,000 persons in a trial comparing 900 mg of rifapentine and 900 mg of isoniazid given once weekly for 12 weeks with a 9-month regimen of daily isoniazid in persons who are at high risk for reactivation tuberculosis. Weiner and his colleagues have presented data that challenge us to determine the optimum dose of rifapentine in the treatment of tuberculosis. This will not be easy, as tuberculosis trials are lengthy and thus need an exceptional commitment of time and money. With tuberculosis still globally out of control, it is urgent to undertake studies that allow us to maximize the benefit from those drugs and drug combinations that are available to treat this worldwide plague. FOOTNOTES Conflict of Interest Statement: F.M.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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