Potent Twice-Weekly Rifapentine-containing Regimens in Murine Tuberculosis

Abstract

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...

Pharmacokinetics and Tolerability of a Higher Rifampin Dose versus the Standard Dose in Pulmonary Tuberculosis Patients

“…Strategies to shorten treatment include further optimization of the dosing of available TB drugs and the evaluation of new antituberculosis drugs (among which the quinolone moxifloxacin seems most promising) (2) or a combination of these (15). Based on available data (4,8), increasing the dose of rifampin seemed a promising means to optimize the response to this drug.…”

New Drugs against Tuberculosis: Problems, Progress, and Evaluation of Agents in Clinical Development

“…The use of rifapentine once weekly has therefore been restricted to HIVnegative pulmonary TB patients without cavitation and with a negative sputum culture after the intensive phase of treatment (63). Higher than standard doses of rifapentine have shown the potency to shorten TB treatment in mice, especially when combined with moxifloxacin (130).…”

“…A higher dose of rifapentine (15 mg/kg) with moxifloxacin (100 mg/kg twice per day) in a once-weekly continuation-phase regimen in mice showed better sterilizing activity than once-weekly rifapentine (15 mg/kg) and isoniazid (75 mg/kg) or twice-weekly rifampin (10 mg/kg) and isoniazid (75 mg/kg) (131). A twice-weekly regimen in mice containing rifapentine (15 or 20 mg/kg), pyrazinamide (300 mg/kg), and moxifloxacin (100 mg/kg), preceded by 2 weeks of daily rifampin (10 mg/kg), pyrazinamide (150 mg/kg), and moxifloxacin (100 mg/kg), resulted in stable cure after 4 months of treatment (130). Substitutions of rifampin (10 mg/kg) by rifapentine (10 mg/kg) and of isoniazid (25 mg/kg) by moxifloxacin (100 mg/kg twice per day) in a daily standard regimen in mice lead to bacillus eradication rates twice as fast as the standard regimen (132).…”

“…A multicenter three-armed REMoxTB trial in which the standard regimen is compared to (i) a regimen of 2RHZM/2RHM and (ii) a regimen of 2RMZE/2RM has recently started. The possibility of combining moxifloxacin with rifapentine, two agents with a long halflife, is explored in the RIFAQUIN trial (see section about rifapentine) (85,130,131,167). Finally, moxifloxacin could be of use in the treatment of latent TB.…”

Enhanced Bactericidal Activity of Rifampin and/or Pyrazinamide When Combined with PA-824 in a Murine Model of Tuberculosis

“…For example, in the current study, the mean lung CFU count at baseline was relatively low at log 10 7.11 Ϯ 0.25, and the response to the standard regimen was somewhat more rapid than usual, with a mean lung CFU count of log 10 1.95 Ϯ 0.28 after 2 months of treatment and a relapse rate of 15% after only 4 months of treatment. In other recent studies in which treatment began at similar mean CFU counts, the response to the same positive control was more limited, with a typical CFU count reduction of approximately log 10 4.5 after 2 months of treatment and relapse rates of 50 to 90% after 4 months of treatment (11,13,14). If these data are not taken into consideration, there is a risk of overestimating the activity of the test regimens in the current study.…”