Multiple-dose pharmacokinetics and safety of trovafloxacin in healthy volunteers.

Abstract

The multiple-dose pharmacokinetics and safety of trovafloxacin (CP-99,219), a new fluoroquinolone antibacterial agent, were evaluated in healthy male volunteers. Trovafloxacin was administered orally at 100 or 300 mg as a single dose followed by a 3 day washout period, and then was dosed once-daily for 14 consecutive days. Multiple serum and urine samples were collected on days 1 and 17 and were analysed for trovafloxacin concentrations by HPLC-UV. Following single doses, the mean Cmax values (mean +/- S.D.) were 1.0 +/- 0.3 and 2.9 +/- 0.4 mg/L for the 100 and 300 mg, respectively; those after 14-day consecutive daily dosing (day 17) were 1.1 +/- 0.2 and 3.3 +/- 0.5 mg/L, respectively. Trovafloxacin was rapidly absorbed and reached Cmax approximately 1 h after dosing. The mean values of T1/2 associated with the 100 and 300 mg doses were 9.2 +/- 1.2 on day 1 and 10.5 +/- 0.7 h on day 17; those after the 300 mg doses were 10.5 +/- 1.4 and 12.2 +/- 1.9 h, respectively. The cumulative urinary recovery of unchanged drug averaged 5.3% of the administered dose. Trovafloxacin renal clearance was 0.43 +/- 0.09 L/h. The free fraction of the drug in plasma was 23.8 +/- 6.1%. The renal clearance, half-life and unbound fraction did not change over the course of 2 weeks of multiple dosing. Steady-state serum concentrations were attained by the third daily dose, with approximately 1.3-fold accumulation. Both doses of trovafloxacin were well tolerated, and no significant changes in any laboratory safety parameters were detected. This study shows that the pharmacokinetics of trovafloxacin are linear and stationary and that steady-state serum concentrations above the MICs for most susceptible pathogens attained.