PHASE-I PILOT-STUDY OF THE EFFECTS OF TROVAFLOXACIN (CP-99,219) ON THE PHARMACOKINETICS OF THEOPHYLLINE IN HEALTHY-MEN

This study examined the effect of trovafloxacin (CP-99,219) on the pha rmacokinetics and pharmacodynamics of a single dose of theophylline, w hen administered to steady-state concentrations. Twelve healthy, nonsm oking male volunteers participated. A 450-mg dose of theophylline was administered at 7:00 AM on day 1. On day 4, volunteers received 300 mg of trovafloxacin (CP-99,219) daily in the morning for 7 days. The 450 -mg dose of theophylline was repeated on day 8 at 7:00 AM concomitantl y with 300 mg of trovafloxacin. Theophylline concentrations in plasma and trovafloxacin in serum were determined using reverse-phase high-pe rformance liquid chromatography. There was no significant difference b etween the geometric mean values for C-max of theophylline, 6.42 mu g/ mL and 6.00 mu g/mL on days 1 and 8, respectively. A change (P = 0.032 ) in the geometric mean of the area under the concentration-time curve extrapolated to infinity (AUC(0-infinity)) for theophylline was noted after trovafloxacin was administered. Mean terminal phase elimination rate constants (K(0)s) were reduced (P = 0.001) by 13% after administ ration of trovafloxacin from day 1 to day 8. In general, changes in th eophylline clearance of less than 20% are unlikely to be of clinical s ignificance. In this study, oral administration of trovafloxacin in 30 0-mg doses to achieve steady-state concentration resulted in an 8.4% i ncrease in the extent of systemic exposure (AUC(0-infinity)) to theoph ylline. Assuming that this AUC change is based on oral clearance and n ot absorption, one would not expect to see clinically significant chan ges in the pharmacokinetics of theophylline. No pharmacodynamic change s resulted from the pharmacokinetic changes of theophylline.