Double-blind evaluation of the safety and pharmacokinetics of multiple oral once-daily 750-milligram and 1-gram doses of levofloxacin in healthy volunteers

The safety and pharmacokinetics of once-daily oral levofloxacin in 16 healthy male volunteers were investigated in a randomized, double-blind, placebo-controlled study. Subjects were randomly assigned to the treatment (n = 10) or placebo group (n = 6). In study period 1,750 mg of levofloxacin or a placebo was administered orally as a single dose on day 1, followed by a washout period on days 2 and 3; dosing resumed for days 4 to 10. Following a 3 day washout period, 1g of levofloxacin or a placebo was administered in a similar fashion in period 2. Plasma and urine levofloxacin concentrations were measured by high-pressure liquid chromatography. Pharmacokinetic parameters were estimated by model-independent methods. Levofloxacin was rapidly absorbed after single and multiple once-daily 750-mg and l-g doses with an apparently large volume of distribution. Peak plasma levofloxacin concentration (C-max) values were generally attained within 2 h postdose. The mean values of C-max and area under the concentration-time curve from 0 to 24 h (AUC(0-24)) following a single 750-mg dose were 7.1 mu g/ml and 71.3 mu g.h/ml, respectively, compared to 8.6 mu g/ml and 90.7 mu g.h/ml, respectively, at steady state. Following the single 1-g dose, mean C-max and AUC(0-24) values were 8.9 mu g/ml and 95.4 mu g.h/ml, respectively; corresponding values at steady state were 11.8 mu g/ml and 118 mu g.h/ml. These C-max and AUC(0-24) values indicate modest and similar degrees of accumulation upon multiple dosing at the two dose levels. Values of apparent total body clearance (CL/F), apparent volume of distribution (V-ss/F), half-life (t(1/2)), and renal clearance (CLR) were similar for the two dose levels and did not vary from single to multiple dosing. Mean steady-state values for CL/F, V-ss/F, t(1/2) and CLR following 750 mg of levofloxacin were 143 ml/min, 100 liters, 8.8 h, and 116 ml/min, respectively; corresponding values for the 1-g dose were 146 ml/min, 105 liters, 8.9 h, and 105 ml/min. In general, the pharmacokinetics of levofloxacin in healthy subjects following 750-mg and 1-g single and multiple once-daily oral doses appear to be consistent with those found in previous studies of healthy volunteers given 500-mg doses. Levofloxacin was well tolerated at either high dose level. The most frequently reported drug-related adverse events were nausea and headache.