Double-Blind Evaluation of the Safety and Pharmacokinetics of Multiple Oral Once-Daily 750-Milligram and 1-Gram Doses of Levofloxacin in Healthy Volunteers

Abstract

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, 1 g 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 1-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 (AUC0–24) following a single 750-mg dose were 7.1 μg/ml and 71.3 μg · h/ml, respectively, compared to 8.6 μg/ml and 90.7 μg · h/ml, respectively, at steady state. Following the single 1-g dose, mean C max and AUC0–24 values were 8.9 μg/ml and 95.4 μg · h/ml, respectively; corresponding values at steady state were 11.8 μg/ml and 118 μg · h/ml. These C maxand AUC0–24 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.

Pharmacokinetics of levofloxacin after single and multiple oral doses in patients undergoing intermittent haemodialysis

“…In the same context, AUC and V ss were higher than those described in healthy subjects administered a single 500 mg dose [13,15]. These pharmacokinetic parameters of patients undergoing IHD after a single dose of 500 mg were similar to those achieved in healthy subjects administered doses ranging between 750 mg and 1000 mg [9,14].…”

“…Results following single oral administration of 500 mg revealed that t 1/2 was prolonged and clearance was decreased compared with the pharmacokinetics of levofloxacin in healthy volunteers [9,[13][14][15]. This discrepancy may be explained by the renal failure of the study subjects impeding drug clearance compared with the non-problematic renal excretion of levofloxacin in healthy subjects.…”

“…The levofloxacin absorption rate following oral administration was assumed to be zero order and elimination was linear and first order. This model has been successfully applied to describe pharmacokinetics of levofloxacin following oral administration in healthy subjects [9,10]. Pharmacokinetic parameters were determined as follows: peak concentration (C max ) and time to reach C max (T max ) were determined directly from the individual concentration-time profiles; area under the concentration-time curve (AUC 0→24 ) at steady state (multiple doses) and with extrapolation to infinity (AUC 0→Inf ) for single doses by use of the linear trapezoidal rule; elimination half-time (t 1/2 ) by the equation ln 2/k (where k is the slope of the concentration-time curve at the terminal log-linear phase); total drug clearance (CL) by the equation dose/AUC 0→Inf (after a single dose) or dose/AUC 0→24 (after multiple doses); apparent distribution volume (V a ) by the non-compartmental equation CL/k; and distribution volume (V ss ) at steady state using standard equations as described previously [11].…”

Pharmacodynamic target attainment analysis against Streptococcus pneumoniae using levofloxacin 500mg, 750mg and 1000mg once daily in plasma (P) and epithelial lining fluid (ELF) of hospitalized patients with community acquired pneumonia (CAP)

“…Probability of achieving AUC 0-24 /MIC all of 100 in P or EL was very low in both patient populations at different doses except in the case of elderly patients receiving levofloxacin in a dose of 1000 mg once daily P/ELF of 78.5%/87.0%. [36]. b Epithelial lining fluid.…”

Intrapulmonary pharmacokinetics and pharmacodynamics of high-dose levofloxacin in healthy volunteer subjects

“…Exceeding the mutant prevention drug concentration may also serve to delay the onset of resistance, as hypothesised by a number of authors [24][25][26][27][28][29][30]. Higher doses (1000 mg) of levofloxacin have been administered safely to healthy volunteers and subjects with acquired immune deficiency syndrome (AIDS) [31,32].…”