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 moxifloxacin-containing 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).

Conclusions: By virtue of the enhanced rifamycin exposure, twice-weekly regimens containing rifapentine (15 or 20 mg/kg) may permit shortening the current treatment duration by 2 mo. Such regimens warrant clinical investigation.

Figures

Figure 1.

Log10 lung cfu counts after 8 wk of therapy in Study 1. All drug regimens included an initial 2 wk of daily (5/7 d) rifampin, isoniazid, and pyrazinamide (RHZ), or rifampin, moxifloxacin, and pyrazinamide (RMZ), followed by 6 wk of twice-weekly (2/7 d) therapy (Table 1). Regimen 1 was administered daily throughout. The cfu count at initiation of treatment (Day 0) was 7.06 log10. * Significant difference (p < 0.01) when compared with standard daily therapy, RHZ. M1 = moxifloxacin 100 mg/kg once daily; M2 = moxifloxacin 100 mg/kg twice daily; PHZ = rifapentine plus isoniazid plus pyrazinamide; PMZ = rifapentine + moxifloxacin + pyrazinamide.

Figure 2.

Log10 lung cfu counts after 2 mo treatment with RHZ (5/7 d), RM2Z (5/7 d), 2 wk RM2Z (5/7 d) + 6 wk P15M2Z (2/7 d; where P = rifapentine; Regimen 10), 2 wk RM2ZH (5/7 d) + 6 wk P15M2Z (2/7 d; Regimen 8), or 2 wk RM2ZH (5/7 d) + 6 wk P15M2ZH (2/7 d; Regimen 9) in Study 2. * Significant linear “exposure-dependent” response for H, p = 0.001.

Figure 3.

Mean rifapentine and rifampin total drug serum concentrations over time in mice administered a single dose or 5 wk of twice-weekly rifapentine (15 mg/kg) or daily rifampin (10 mg/kg).