Zee M. Look

Determination of cefixime in biological samples by reversed-phase high-performance liquid chromatography

A simple, accurate and precise isocratic reversed-phase high-performance liquid chromatographic method has been developed and validated for the determination of a new cephalosporin in human serum and urine. Human serum samples, calibration standards and quality control samples (250 microliter) were combined with an equal volume of 6% trichloroacetic acid (TCA). Human urine (0.1 ml) was combined with 6% TCA solution containing the internal standard. The compounds were detected by ultraviolet absorbance set to 280 nm for the serum assay and 313 nm for the urine assay. The method for the determination of cefixime in serum was linear from 100 ng/ml to 30.0 micrograms/ml (r = 0.999), and for the urine assay from 5 micrograms/ml to 100 micrograms/ml (r = 0.999). The minimum reportable quantity for the serum assay was 0.05 microgram/ml. The within- and between-day assay variation for both assays were found to be less than 10% in an extensive assay validation scheme. Results of a storage stability study indicated that human serum and urine samples could be safely stored for up to six months at -18 degrees C and three months at -10 degrees C, respectively.

Pharmacokinetics of Cefixime After Once‐a‐Day and Twice‐a‐Day Dosing to Steady State

The pharmacokinetics of cefixime (CL 284,635; FK027), a new orally active broad‐spectrum cephalosporin, were determined in 26 healthy volunteers, after multiple 200‐mg twice‐a‐day (group 1; N = 13) or 400‐mg once‐a‐day (group 2; N = 13) dosing for 15 days. On study days 1, 8, and 15, mean peak serum concentrations (Cmax) were 1.67, 1.75, and 1.87 μg/mL, respectively, for group 1 and 2.76, 3.04, and 2.67, respectively, for group 2. Over the 15‐day period, mean trough serum concentrations were, on average, 0.40 and 0.08 μg/mL for groups 1 and 2, respectively. Comparison (ANOVA) of serum and urinary excretion pharmacokinetic parameters for cefixime on days 1, 8, and 15 found no significant (P > .05) differences for either group except for a small but significantly (P < .05) earlier time to reach Cmax and higher renal clearance on days 8 and 15 in group 1. These differences, however, are not clinically significant. On study days 1, 8, and 15, mean Cmax and AUC0‐r values for Group 2 were about 1.5 to 2.2 time those for Group 1. Urinary excretion of cefixime accounted for 11.9 to 14.5% and 9.9 to 12.4% of the dose in groups 1 and 2, respectively, over the 15‐day study. Overall, there was no accumulation of cefixime in serum or urine nor was there a reduction in serum concentrations or urinary amounts over the 15‐day dosing period when the drug was given either as a 200‐mg twice‐a‐day or 400‐mg once‐a‐day dosing regimen.

Bioequivalency of solid oral dosage forms of cefixime

Abstract A study was performed in 24 healthy subjects to determine whether tablet and capsule formulations of cefixime (CL 284,635; FK027), a new oral cephalosporin, given as a single 400 mg dose, were bioequivalent to one another and to a reference oral solution. Mean values of C max in serum were 3.87, 3.39, and 3.82 μg/ml after tablet, capsule and solution doses, respectively. Comparison (ANOVA) of the pharmacokinetic parameters showed significantly ( P 0 → ∞ and C max values for the capsule than for the tablet; however, the mean differences were less than 16%. All pharmacokinetic parameters for the tablet, except for a significantly larger MRT ni and t max , were comparable to those for the solution. The bioavailability of cefixime based on AUC 0 → ∞ and 24-h urinary recovery data from the tablet dosage form was slightly better (mean differences 14–16%) than from the capsule and virtually identical to that after the oral solution. The statistical power of the study was greater than 90% to detect a difference in AUC 0 → ∞ values of 20%. Overall, based on AUC 0 → ∞ comparisons, the results show that the tablet, capsule and oral reference solution are bioequivalent to one another.

Dose-dependent pharmacokinetics of a new oral cephalosporin, cefixime, in the dog.

Cefixime (CL 284,635; FK 027) is a new third-generation oral cephalosporin. To study dose-dependent pharmacokinetics of cefixime in dogs, two balanced four-way crossover studies were conducted. In the first study, oral doses of 50, 100, and 200 mg/kg and an intravenous dose of 50 mg/kg cefixime were administered. In the second study, oral doses of 6.25, 12.5, and 25 mg/kg and an intravenous dose of 12.5 mg/kg cefixime were administered to the same dogs. A period of 1 month separated the two studies. When the two intravenous doses were compared (i.e., 12.5 and 50 mg/kg), a twofold increase in clearance and volume of distribution was observed after the higher dose. The oral systemic bioavailability in the dose range 6.25–50 mg/kg was 55%. It decreased to 44% at 100 mg/kg and 27% at 200 mg/kg. The average peak serum concentrations ranged from 15.8 µg/ml at 6.25 mg/kg to 119 µg/ml at 200 mg/kg. Within this concentration range, the fraction of free drug in serum (unbound to proteins) increased from 7 to 25%. This concentration-dependent protein binding was primarily responsible for changes in total clearance, volume of distribution, and bioavailability of the drug in dogs.

Saturable Processes Affecting Renal Clearance of Cefixime in Dogs

The pharmacokinetics of cefixime, a new orally active cephalosporin, was studied after an intravenous dose of 50 mg/kg to four beagle dogs. Cefixime was shown to exhibit concentration dependent serum protein binding and saturable tubular reabsorption. The drug was excreted mainly in the urine, the net result of glomerular filtration and saturable tubular reabsorption. The experimental results were analyzed by model independent pharmacokinetic equations and with theoretical models describing renal clearance. Modification of the models, based on observed data, was proposed. The experimental methods employed and the pharmacokinetic approach offered in this study can be applied to drugs that exhibit concentration dependent protein binding and saturable renal elimination processes.