Repeated administration of high-dose intermittent rifapentine reduces rifapentine and moxifloxacin plasma concentrations

Abstract

Moxifloxacin- and rifapentine-based regimens are under investigation for the treatment of tuberculosis. However, rifapentine may induce enzymes that metabolize moxifloxacin, resulting in decreased moxifloxacin concentrations. In this phase I, two-period, sequential-design study, 13 subjects received 400 mg moxifloxacin daily for 4 days followed by daily moxifloxacin coadministered with 900 mg rifapentine thrice weekly. Pharmacokinetic analyses were performed after the 4th and 19th doses of moxifloxacin and after the 1st and 7th doses of rifapentine. For moxifloxacin, the mean area under the concentration-time curve from 0 to 24 h (AUC(0-24)) decreased by 17.2% (P = 0.0006) when the drug was coadministered with rifapentine, and the mean half-life (t(1/2)) decreased from 11.1 to 8.9 h (P = 0.0033). For rifapentine, the mean AUC(0-48) after seven thrice-weekly doses decreased by 20.3% (P = 0.0035) compared to the AUC(0-48) after the first dose, and the mean t(1/2) decreased from 18.5 to 14.8 h (P = 0.0004). The AUC(0-48) for the 25-desacetyl-rifapentine metabolite diminished 21%. Two days after completing the study drugs, one subject developed a fever and hepatitis, and another developed a flu-like illness with a rash. In conclusion, rifapentine modestly reduced moxifloxacin concentrations. Changes consistent with rifapentine autoinduction of metabolism were seen. Adverse reactions in two subjects may have represented rifamycin hypersensitivity syndrome, although some features were atypical.

Figures

FIG. 1.

Schematic of the dosing regimen and pharmacokinetic sample collection.

FIG. 2.

Steady-state mean MXF plasma concentrations versus time curves after four doses of MXF dosed at 400 mg once daily (▴) and after 15 days of 400 mg MXF once daily plus 900 mg RPT thrice weekly (•). Values shown represent arithmetic means with standard error bars.

FIG. 3.

(A) Mean plasma RPT concentrations versus time of RPT after a single 900-mg dose (▵) versus after seven doses of 900 mg thrice weekly (○). (B) Mean plasma 25-desacetyl-RPT concentrations versus time after a single 900-mg dose of RPT (▵) versus after seven doses of 900 mg given thrice weekly (○). Values shown represent arithmetic means with standard error bars.