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Abstract
Levofloxacin is a broad-spectrum antibiotic with activity against gram-positive and -negative bacteria. This study compared the pharmacokinetics (PK) and evaluated the bioequivalence of two levofloxacin 100-mg tablet formulations. An open, randomized, two-way crossover study was conducted in 28 healthy volunteers. The reference (Cravit Tab 100-mg, Jeil) or test (Levobacter Tab, Seoul) formulation was administered and serial blood samples were collected over 24 h for PK analysis. Levofloxacin plasma concentrations were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The correlation of levofloxacin concentration at various time points with the area under the concentration time-curve over the time interval from 0 extrapolated to infinity (AUCinf) was estimated to determine the best reflected time point. The average half-life, maximum plasma concentration (Cmax), and AUClast were comparable. The 90% confidence intervals (CIs) of the geometric mean ratio (GMR test/reference) of AUClast and C max were 0.8200–1.0633 and 0.9474–1.0643 respectively. Both formulations were tolerated with no clinically relevant safety issues. Plasma levofloxacin concentrations at various time points correlated well with the AUCinf, and showed high correlation coefficients (r > 0.7, P < 0.001) for both drugs 8 and 12 h after administration. Both formulations showed similar PK profiles while levofloxacin plasma levels after administration indicated their bioequivalence. The Cmax and AUClast GMR 90% CIs were 0.80–1.25. Moreover, 12 h was the best time point to predict the AUCinf and therefore suitable for therapeutic drug monitoring.
References
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Figure 1.
Mean plasma concentration–time curve for test and reference formulations of 100-mg levofloxacin after a single oral dose N = 24, error bars represent standard deviation (SD); Left and right linear and log scale, respectively.
Table 1.
Demographic data of study population of healthy Korean volunteers
| Sequence | Total (N=24) | P-value | ||
|---|---|---|---|---|
| Group A (N=12) | Group B (N=12) | |||
| Age (yr) | 24.0±3.3 | 25.2±3.0 | 24.6±3.2 | 0.38 |
| Height (cm) | 175.6±5.8 | 173.0±6.6 | 174.3±6.2 | 0.32 |
| Weight (kg) | 70.4±9.3 | 65.8±9.2 | 68.1±9.3 | 0.24 |
Table 2.
Pharmacokinetic parameters following single oral administration of two 100-mg formulations of levofloxacin (test and reference drugs) in healthy Korean volunteers
| Parameters | Test drug (N=24) | Reference drug (N=24) | Geometric mean ratio (90% CI)b | ||
|---|---|---|---|---|---|
| Mean (SD) | CV (%) | Mean (SD) | CV (%) | ||
| Tmax (h)a | 1.00 (0.33–2.50) | 1.00 (0.67–4.00) | – | ||
| Cmax (μg/mL) | 1.61 (0.75) | 46.46 | 1.66 (0.47) | 28.47 | 0.9338 (0.8200–1.0633) |
| AUClast (h∙μg/mL) | 7.54 (1.68) | 22.33 | 7.53 (1.79) | 23.75 | 1.0041 (0.9474–1.0643) |
| AUCinf (h∙μg/mL) | 9.03 (1.71) | 19.89 | 9.07 (1.80) | 18.96 | 0.9974 (0.9594–1.0370) |
| Half-life (h) | 6.03 (1.66) | 27.59 | 6.15 (1.52) | 24.64 | – |
| CL/F (L/h) | 11.47 (2.21) | 19.31 | 11.46 (2.30) | 20.08 | – |
Values are presented as mean ± standard deviation (SD) and coefficient of variation (%C.V). Tmax, time to peak concentration; Cmax, peak plasma concentration; AUClast, area under the plasma concentration-time curve from 0 to the last measurable time; AUCinf, area under the plasma drug concentration-time curve over the time interval from 0 extrapolated to infinity; CL/F, apparent clearance;
Table 3.
Correlation between plasma levofloxacin concentration at various time-points and area under the concentration time-curve over the time interval from 0 extrapolated to infinity (AUCinf) of reference and test drugs
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