Effects of rifampin and multidrug resistance gene polymorphism on concentrations of moxifloxacin

Abstract

Treatment regimens combining moxifloxacin and rifampin for drug-susceptible tuberculosis are being studied intensively. However, rifampin induces enzymes that transport and metabolize moxifloxacin. We evaluated the effect of rifampin and the human multidrug resistance gene (MDR1) C3435T polymorphisms (P-glycoprotein) on moxifloxacin pharmacokinetic parameters. This was a single-center, sequential design study with 16 volunteers in which sampling was performed after four daily oral doses of moxifloxacin (400 mg) and again after 10 days of combined rifampin (600 mg) and moxifloxacin. After daily coadministration of rifampin, the area under the concentration-time curve from 0 to 24 h (AUC(0-24)) for moxifloxacin decreased 27%. Average bioequivalence between moxifloxacin coadministered with rifampin and moxifloxacin alone was not demonstrated: the ratio of geometric means (RGM) of the moxifloxacin AUC(0-24) was 73.3 (90% confidence intervals [CI], 64.3, 83.5) (total P value, 0.87 for two one-sided t tests). Peak moxifloxacin concentrations, however, were equivalent: the RGM of the maximum concentration of the drug in serum was 93.6 (90% CI, 80.2, 109.3) (total P value, 0.049). Concentrations of the sulfate conjugate metabolite of moxifloxacin were increased twofold following rifampin coadministration (AUC(0-24), 1.29 versus 2.79 mug.h/ml). Concomitant rifampin administration resulted in a 27% decrease in the mean moxifloxacin AUC(0-24) and a marked increase in the AUC(0-24) of the microbiologically inactive M1 metabolite. Additional studies are required to understand the clinical significance of the moxifloxacin-rifampin interaction.

Figures

FIG. 1.

Mean plasma moxifloxacin (A), moxifloxacin metabolite M1 (B), and moxifloxacin metabolite M2 (C) concentrations versus time (hours) resulting from an oral dose of moxifloxacin (400 mg) without (▵) or with (•) coadministered rifampin (600 mg) at steady state (pharmacokinetic sampling at days 4 and 14 of moxifloxacin administered daily; n = 16). Values are arithmetic means; error bars, standard errors. The lower limit of quantitation was 0.0156 μg/ml for M1 and 0.026 μg/ml for M2.

FIG. 2.

Mean plasma moxifloxacin concentration versus time (hours) resulting from an oral dose of moxifloxacin (400) mg with (A) or without (B) coadministered rifampin (600 mg) at steady state grouped by MDR1 3435 CC (•) versus other genotypes (▵). Values are arithmetic means; error bars, standard errors.