Pharmacokinetic Interactions between Theophylline and Prulifloxacin in Healthy Volunteers

Abstract

Objective: To determine the potential influence of prulifloxacin (AF3012, NM441), a new antibacterial fluoroquinolone, on the pharmacokinetics of theophylline.

Subjects and Methods: 12 healthy volunteers received a single oral dose of theophylline (6 mg/kg) in a control session and, thereafter, on the first and seventh days of an eight-day treatment regimen with oral prulifloxacin 600mg once daily. Plasma levels of theophylline were determined by a validated high performance liquid Chromatographic method in samples collected for up to 48 hours after each dose.

Results: Compared with the control session, prulifloxacin treatment was associated with a statistically significant increase in areas under the concentration-time curve (from a baseline value of 137 ± 9 mg/L·h to 157 ± 8, and 159 ± 9 mg/L·h on the first and 7th day, respectively; p < 0.01) and a prolongation in theophylline half-life (from 7.1 ± 0.3 hours at baseline to 8.1 ± 0.4, and 8.0 ± 0.4 hours on the first and 7th day, respectively; p < 0.01) with a consequent 15% decrease in theophylline apparent oral clearance (from 45.7 ± 2.8 ml/h/kg to 39.2 ± 2.0, and 39.0 ±2.1 ml/h/kg on the first and 7th day, respectively; p < 0.01). No differences were observed for peak plasma concentrations, time to peak concentrations and apparent volume of distribution.

Conclusion: These findings indicated that prulifloxacin decreases the elimination of theophylline, presumably by inhibiting cytochrome P450 1A2-mediated drug oxidation. Although this interaction is not expected to have important clinical implications, monitoring of possible changes in serum theophylline levels is recommended, as with all patients receiving theophylline in combination with agents potentially affecting drug metabolism.