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Influence of rifampin on fleroxacin pharmacokinetics
J Schrenzel1, P Dayer, T Leemann
1Division of Infectious Diseases, Geneva University Hospital, Switzerland.
Abstract:
Staphylococcus aureus infections have been successfully treated in animal models with the combination of fleroxacin and rifampin. We studied the influence of rifampin, a potent cytochrome P-450 inducer, on the pharmacokinetics and biotransformation of fleroxacin in 14 healthy young male volunteers. Subjects were given 400 mg of fleroxacin orally once a day for 3 days to reach steady state. After a wash-out period of 2 days, the same subjects received 600 mg of rifampin orally once daily for 7 days. On days 5 to 7 of rifampin treatment, 400 mg of fleroxacin was again administered once daily. Concentrations of fleroxacin as well as its two major urinary metabolites, N-demethyl- and N-oxide-fleroxacin, in plasma and urine were determined by reverse-phase high-performance liquid chromatography. The extent of hepatic enzyme induction by rifampin was confirmed by a significant increase of 6-beta-hydroxycortisol urinary output from 160.8 +/- 41.4 to 544.8 +/- 120.7 micrograms/4 h. There were no significant changes in the peak fleroxacin concentration in plasma (6.3 +/- 1.2 versus 6.2 +/- 1.9 mg/liter), time to maximum concentration of fleroxacin in plasma (1.1 +/- 0.9 versus 1.3 +/- 1.1 h), or renal clearance (58.3 +/- 16.4 versus 61.9 +/- 19.2 ml/min). The area under the curve AUC (71.4 +/- 15.8 versus 62.2 +/- 13.7 mg.h/liter) and the terminal half-life of fleroxacin (11.4 +/- 2.2 versus 9.2 +/- 1.1 h) decreased (P < 0.05), while the total plasma clearance increased from 97.7 +/- 21.6 to 112.3 +/- 25.8 ml/min (P < 0.01). Despite being statistically significant, this 15% increase in total plasma clearance does not appear to be clinically relevant. Metabolic clearance by N demethylation was increased ( 6.9 +/- 2.4 versus 12.5 +/- 3.2 ml/min; P < 0.01), whereas clearance by N oxidation did not change (5.8 +/- 1.1 versus 5.8 +/- 1.5 ml/min). Fleroxacin elimination was slightly increased (about 15%) through induction of metabolic clearance to N-demethyl-fleroxacin. Since fleroxacin levels remained above the MIC for 90% of the tested isolates of methicillin-susceptible S. aureus for at least 24 h, dose adjustment does not appear necessary, at least for short-term treatments.
Insights
Rifampin, a potent enzyme inducer, slightly increased fleroxacin clearance by 15% in healthy volunteers. This change did not significantly impact fleroxacin levels, suggesting no dose adjustment is needed for short-term Staphylococcus aureus treatments.
Area of Science:
- Pharmacology
- Drug Metabolism
- Infectious Diseases
Background:
- Staphylococcus aureus infections are a significant clinical concern.
- Combination therapy with fleroxacin and rifampin shows promise in animal models.
- Rifampin is a known inducer of cytochrome P-450 enzymes, potentially affecting drug metabolism.
Purpose of the Study:
- To investigate the pharmacokinetic and biotransformation effects of rifampin on fleroxacin in healthy male volunteers.
- To determine if rifampin alters fleroxacin plasma concentrations and elimination pathways.
- To assess the clinical relevance of any observed changes in fleroxacin pharmacokinetics.
Main Methods:
- 14 healthy young male volunteers received fleroxacin (400 mg daily) to steady state.
- A washout period was followed by rifampin administration (600 mg daily) for 7 days.
- Fleroxacin (400 mg daily) was readministered during the latter part of rifampin treatment.
- Plasma and urine concentrations of fleroxacin and its metabolites were quantified using HPLC.
- Hepatic enzyme induction was confirmed by measuring 6-beta-hydroxycortisol output.
Main Results:
- Rifampin significantly increased urinary 6-beta-hydroxycortisol output, confirming hepatic enzyme induction.
- No significant changes were observed in peak plasma fleroxacin concentration or time to reach it.
- Total plasma clearance of fleroxacin increased by approximately 15% (P < 0.01), while AUC and half-life decreased (P < 0.05).
- Metabolic clearance via N-demethylation increased significantly (P < 0.01), while N-oxidation remained unchanged.
- Despite a 15% increase in clearance, fleroxacin levels remained above the MIC90 for methicillin-susceptible S. aureus for at least 24 hours.
Conclusions:
- Rifampin induces metabolic clearance of fleroxacin, primarily through N-demethylation.
- The observed increase in fleroxacin total plasma clearance is modest and likely not clinically significant.
- Current dosing of fleroxacin appears adequate for short-term treatment of susceptible S. aureus infections, even with concurrent rifampin use.