To investigate the bioequivalence and the population pharmacokinetics of cefuroxime lysine and cefuroxime sodium in healthy beagle dogs. A randomized 2-period crossover design in 18 healthy beagle dogs after receiving 20, 40, and 80 mg/kg of cefuroxime lysine or cefuroxime sodium was conducted. A 3-compartment open model was used as the basic model for the population pharmacokinetic study. Both of the antibiotics exhibited dose-proportional pharmacokinetics over the dose range of 20–80 mg/kg. The mean relative bioavailability of cefuroxime lysine versus cefuroxime sodium was 1.05 (range, 0.71 to 1.42), with a significant difference between males and females. The estimates of population pharmacokinetic of CL,
Cefuroxime sodium is a semisynthetic, broad-spectrum, and considered as a second-generation cephalosporins antibiotic agent for parenteral administration. This antibiotic has been widely used for the treatments for patients having infections of soft tissue, respiratory tract, urinary tract, genital tract, central nervous system, and bone and joint tissues [
In general, cefuroxime sodium, formulated as a lyophilised crystalline powder, is administered by intravenous, intramuscular, or intraperitoneal injection routes. The pharmacokinetic properties of cefuroxime sodium have been determined in several species, including goats, calves, rats, and humans [
Eighteen healthy beagle dogs (gender in half, 10.40–14.25 kg, aged 9–14 months) were obtained from the Experimental Animal Research and Development Center of Guangzhou Institute of Pharmaceutical Industry (Guangzhou, China), and they were housed individually in the stainless-steel cages in a controlled environment. Filtered tap water and a standard animal diet were available
The study design was a randomized 2-period crossover using a double-blind, parallel-group, ascending-single-dose, and a week washout period between the treatments. Three dosages (containing 20, 40, 80 mg/kg according to cefuroxime) of cefuroxime sodium (purity: 98.0%, GlaxoSmithKline Manufacturing S.p.A., Italy) and cefuroxime lysine (purity: 98.8%, Shandong Luoxin Pharmacy Stock Co., Ltd., Shandong, China) were dissolved in 0.9% NaCl sterile solution. The drugs were infused constantly for 30 min with an infusion pump via the hindlimb vein of the dogs. The dose was selected based on the amount normally administered to human in clinic. The blood samples (1 mL) were withdrawn via the foreleg vein into 1.5 mL heparinized tubes at −0.5 (to serve as a control), −0.42, −0.33, −0.25, 0 (the end of infusion) and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12 h after the end of the infusion. The plasma samples were immediately centrifuged at 3500 g for 10 min and stored at −80°C until analysis.
A triple-quadrupole tandem mass spectrometer (Micromass Quattro micro API mass spectrometer, Waters Corp., Milford, MA, USA) equipped with electrospray ionization (ESI) interface was used for analytical detection [
Pharmacokinetic parameters of cefuroxime lysine and cefuroxime sodium were calculated from plasma concentration-time curves using WinNonlin 5.2 (Pharsight Corporation, Mountain View, CA, USA) and DRUG AND STATISTICS software (DAS, version 2.1.1, Mathematical Pharmacology Professional Committee of China) by noncompartmental and compartmental modeling approaches. All values were averaged across different individuals and their standard errors were calculated.
For each subject, the maximum plasma concentration
In order to select the basic model for the population pharmacokinetic analysis, WinNonlin and DAS programs were used here to perform classic compartmental pharmacokinetic analysis. One-, two-, and three-compartment open model were employed to describe the observed data, respectively, and the best one was selected as the basic model of population pharmacokinetics.
A total of 504 plasma samples were used to establish the population pharmacokinetic model using the nonlinear mixed effects modeling (NONMEM) program (version 7.1, GloboMax LLC, Ellicott City, MD) with the fixed factors of dose, age, body weight, and gender as covariates [
The statistical analyses were performed by using SPSS software (version 16.0; SPSS Inc., Chicago, IL). A one-way analysis of variance (ANOVA) was used to determine the difference in different formulations, dosages, and genders. Bioequivalence of cefuroxime lysine and cefuroxime sodium was assessed by calculating 90% confidence intervals of the geometric mean ratios for
Each dog was individually weighted at 1 week and 2 week, and the demographic characteristics of the subjects were listed in Table
Demographic of the drug administrated for 18 beagle dogs.
Antibiotics (mg/kg)a | Sexb | Age (m)c | Weight (kg)c | |
---|---|---|---|---|
1 week | 2 week | |||
20 | M | 11.3 ± 0.58 | 13.6 ± 0.40 | 14.7 ± 0.25 |
F | 11.0 ± 0 | 12.9 ± 1.18 | 13.2 ± 1.22 | |
40 | M | 10.3 ± 1.15 | 13.0 ± 1.52 | 14.0 ± 1.67 |
F | 12.0 ± 1.73 | 13.0 ± 2.08 | 13.6 ± 1.77 | |
80 | M | 12.3 ± 2.89 | 11.7 ± 0.35 | 12.7 ± 0.71 |
F | 11.0 ± 2.65 | 10.9 ± 0.64 | 11.4 ± 0.72 |
a: The administrated antibiotics (both cefuroxime forms).
b: M: male, F: female.
c: Data are listed as means ± SD, where
The pharmacokinetic parameters of cefuroxime lysine, or cefuroxime sodium, were calculated by noncompartment model via WinNonlin and DAS: these results were listed in Tables
Noncompartmental pharmacokinetic parameters obtained for cefuroxime lysine and cefuroxime sodium by using the WinNonlin analysis.
Parameter | Cefuroxime sodium | Cefuroxime lysine | ||||
---|---|---|---|---|---|---|
20 (mg/kg) | 40 (mg/kg) | 80 (mg/kg) | 20 (mg/kg) | 40 (mg/kg) | 80 (mg/kg) | |
|
0.52 ± 0.18 | 0.63 ± 0.18 | 0.51 ± 0.26 | 0.53 ± 0.19 | 0.77 ± 0.08 | 0.57 ± 0.29 |
|
1.50 ± 0.63 | 1.21 ± 0.43 | 1.29 ± 0.39 | 1.46 ± 0.57 | 0.91 ± 0.11 | 1.09 ± 0.35 |
|
0.66 ± 0.24 | 0.62 ± 0.33 | 0.60 ± 0.18 | 0.65 ± 0.28 | 0.41 ± 0.07 | 0.48 ± 0.13 |
CL (L/h/kg) | 0.31 ± 0.05 | 0.34 ± 0.06 | 0.32 ± 0.04 | 0.31 ± 0.03 | 0.31 ± 0.04 | 0.32 ± 0.07 |
MRT0-∞ (h) | 1.86 ± 0.78 | 1.54 ± 0.21 | 1.32 ± 0.12 | 1.85 ± 0.48 | 1.39 ± 0.12 | 1.43 ± 0.22 |
|
0.63 ± 0.44 | 0.54 ± 0.10 | 0.46 ± 0.10 | 0.79 ± 0.60 | 0.50 ± 0.00 | 0.54 ± 0.10 |
|
41.05 ± 12.28 | 84.20 ± 19.15 | 186.9 ± 29.6 | 40.37 ± 15.8 | 92.46 ± 19.3 | 175.7 ± 48.7 |
AUC0-∞ (mg |
65.41 ± 11.7 | 121.5 ± 23.8 | 256.5 ± 33.6 | 66.04 ± 6.45 | 130.9 ± 18.3 | 259.3 ± 56.6 |
AUMC0-∞ | 126.2 ± 77.1 | 187.2 ± 41.2 | 341.9 ± 71.1 | 123.3 ± 36.1 | 181.1 ± 23.3 | 371.9 ± 98.6 |
|
2.05 ± 0.61 | 2.10 ± 0.48 | 2.34 ± 0.37 | 2.02 ± 0.79 | 2.31 ± 0.48 | 2.20 ± 0.61 |
AUCadjusted | 3.27 ± 0.58 | 3.04 ± 0.59 | 3.21 ± 0.42 | 3.30 ± 0.18 | 3.27 ± 0.46 | 3.24 ± 0.71 |
The denotations are
Noncompartmental pharmacokinetic parameters obtained for cefuroxime lysine and cefuroxime sodium by using DAS analysis.
Parameter | Cefuroxime sodium | Cefuroxime lysine | ||||
---|---|---|---|---|---|---|
20 (mg/kg) | 40 (mg/kg) | 80 (mg/kg) | 20 (mg/kg) | 40 (mg/kg) | 80 (mg/kg) | |
|
0.56 ± 0.09 | 0.72 ± 0.16 | 0.50 ± 0.30 | 0.62 ± 0.13 | 0.80 ± 0.17 | 0.77 ± 0.30 |
|
1.27 ± 0.21 | 1.01 ± 0.23 | 1.48 ± 0.86 | 1.15 ± 0.20 | 0.90 ± 0.21 | 0.98 ± 0.28 |
|
0.58 ± 0.14 | 0.46 ± 0.12 | 0.63 ± 0.31 | 0.51 ± 0.08 | 0.41 ± 0.11 | 0.42 ± 0.07 |
CL (L/h/kg) | 0.31 ± 0.05 | 0.34 ± 0.06 | 0.32 ± 0.04 | 0.31 ± 0.02 | 0.31 ± 0.04 | 0.32 ± 0.07 |
MRT (h) | 1.83 ± 0.79 | 1.54 ± 0.21 | 1.32 ± 0.11 | 2.11 ± 0.62 | 1.38 ± 0.13 | 1.42 ± 0.20 |
|
0.63 ± 0.44 | 0.54 ± 0.10 | 0.46 ± 0.10 | 0.79 ± 0.60 | 0.50 ± 0.00 | 0.54 ± 0.10 |
|
41.05 ± 12.28 | 84.20 ± 19.15 | 186.9 ± 29.6 | 40.37 ± 15.8 | 92.46 ± 19.3 | 175.7 ± 48.7 |
AUC0-∞ (mg |
65.35 ± 11.7 | 121.6 ± 23.5 | 256.5 ± 33.4 | 65.63 ± 3.61 | 130.8 ± 18.3 | 259.2 ± 56.6 |
AUMC0-∞ | 124.3 ± 75.7 | 187.8 ± 39.2 | 340.4 ± 67.1 | 138.4 ± 40.1 | 180.1 ± 23.6 | 369.7 ± 98.6 |
|
2.05 ± 0.61 | 2.10 ± 0.48 | 2.34 ± 0.37 | 2.02 ± 0.79 | 2.31 ± 0.48 | 2.20 ± 0.61 |
AUCadjusted | 3.27 ± 0.58 | 3.04 ± 0.59 | 3.21 ± 0.42 | 3.28 ± 0.18 | 3.27 ± 0.46 | 3.24 ± 0.71 |
The denotations are
Plots of
In order to investigate the relative bioavailability and bioequivalence of cefuroxime lysine and cefuroxime sodium, the ratio of dose-normalized AUC (AUC0–∞/dose) between the two antibiotics was considered as the relative bioavailability. The average AUC0–∞/dose for cefuroxime lysine and cefuroxime sodium was 3.28 ± 0.18, 3.27 ± 0.46, 3.24 ± 0.71 h/L and 3.27 ± 0.58, 3.04 ± 0.59, 3.21 ± 0.42 h/L at three different dosages, that are, 20, 40, and 80 mg/kg, respectively (Tables
Relative bioavailability of each subject for male and female dogs. The values were derived from the ratio of dose-normalized AUC (AUC0–∞/dose) as listed in Figure
By the two one-side
In a drug concentration-time curve, a nonlinear relationship between drug concentration in plasma and time was observed (Figure
The linear regression equation of cefuroxime lysine and cefuroxime sodium calculated by predicted/observed drug concentrations with a 3-compartment open model.
Dose | Cefuroxime sodium | Cefuroxime lysine | ||
---|---|---|---|---|
mg/kg | Regression equation |
|
Regression equation |
|
20 |
|
0.9885 |
|
0.9697 |
40 |
|
0.9775 |
|
0.9940 |
80 |
|
0.9918 |
|
0.9843 |
The curves of mean plasma concentrations versus time for cefuroxime lysine (a) and cefuroxime sodium (b) were calibrated following 30 min of infusion The administrated drug concentrations were indicated. The plasma was obtained in different time periods. 10
A 3-compartment open model of predicted versus observed drug concentration in the plasma of cefuroxime lysine (a) or cefuroxime sodium (b) under 20 mg/kg of drug administration. The insert showed that the plot of residuals (observed value − predicted) differs at different time points.
In addition, the population pharmacokinetic parameters of cefuroxime lysine and cefuroxime sodium were estimated and listed in Table
Population pharmacokinetic parameter estimates of cefuroxime lysine and cefuroxime sodium in dog plasma after intravenous infusion in 30 min (20, 40, 80 mg/kg) obtained by 3-compartment pharmacokinetic model.
Parameter | Cefuroxime lysine | Cefuroxime sodium | ||||
---|---|---|---|---|---|---|
Value | RSE (%) |
|
Value | RSE (%) |
| |
Cl (mL/h) | 3.74 | 13.5 | 0.035 | 4.10 | 18.2 | 0.0173 |
|
1.70 | 6.3 | 0.881 | 1.00 | 19.1 | 0.626 |
|
29.5 | 3.5 | 1.77 | 38.5 | 25.7 | 0.47 |
|
3.58 | 14.2 | — | 4.19 | 9.5 | 0.0056 |
|
0.308 | 26.4 | — | 0.0587 | 29.1 | — |
|
158 | 22.1 | — | 13.6 | 27.6 | 0.0029 |
| ||||||
Residual variability | ||||||
|
0.0501 | 22.4 (CV%) | 0.0686 | 26.2 (CV%) | ||
|
0.0029 | 0.0541 (SD) | 0.0038 | 0.0619 (SD) |
The denotations are RSE (%): relative standard error;
The population pharmacokinetic of cefuroxime lysine and cefuroxime sodium in dogs. (a): Experimental versus population-predicted plasma concentrations was generated from the population pharmacokinetic. The values for calculation were from Figure
The present study evaluated the linear pharmacokinetics, gender-related pharmacokinetic profiles and bioequivalence for
The pharmacokinetic properties of cefuroxime sodium have been extensively studied with the most appropriate pharmacokinetic model of a 2-compartment model [
In summary, this intravenous infusion demonstrated that the pharmacokinetic profiles of both antibiotics were similar. Further studies are required to determine the tissue distribution, as to provide a better understanding of its distribution and elimination in the body. The values of AUC were proportional to dose administrated, except the values of CL and
Terminal elimination half life
Maximum plasma concentration
Time to arrive at the
The apparent volume of distribution at steady state
Central volume of distribution
Two peripheral volumes of distribution
Inter-compartmental clearances
Total body systemic clearance
Mean residence time
Area under the curve to the last measured point
Area under the plasma concentration time curve from 0 h to infinite time
Coefficient of variation.
The authors would like to thank Professor Karl Tsim of Hong Kong University of Science and Technology for his comment on this paper. This work was supported by the National Key Scientific Project for New Drug Discovery and Development (no. 2009ZX09301-012).