Comparison of plasma pharmacokinetics and bioavailability of ceftiofur sodium and ceftiofur hydrochloride in pigs after a single intramuscular injection

Abstract

Ceftiofur sodium, a broad-spectrum cephalosporin, is active against gram-positive and gram-negative pathogens of veterinary importance. Two studies were designed to compare the intramuscular bioavailability of the current sodium salt and the new hydrochloride salt in pigs at doses of either 3 mg or 5 mg ceftiofur equivalents (CE)/kg body weight. Twenty-six healthy young pigs were selected for these two-period, two-treatment crossover studies, 12 for the 3 mg/kg study and 14 for the 5 mg/kg study. Each animal received one intramuscular (i.m.) injection of ceftiofur sodium and one i.m. injection of ceftiofur hydrochloride with a 14-day washout period between the two treatments. Blood samples were collected serially for up to 96 h postinjection. Plasma samples were then analysed using a validated assay that measures ceftiofur and all desfuroylceftiofur-related metabolites by high-performance liquid chromatography. In the 3 mg/kg dosage study, average maximum plasma concentration (C(max)) after administration of ceftiofur sodium was 15.8+/-3.40 microg/mL at 0.4-4 h after injection. After administration of ceftiofur hydrochloride, the C(max) was 11.8+/-1.67 microg/mL at 1-4 h after injection. Concentrations of ceftiofur and metabolites 72 h after the injection were 0.392+/-0.162 microg/mL for ceftiofur hydrochloride and 0.270+/-0.118 microg/mL for ceftiofur sodium. The mean area under the curve (AUC), from time 0 to the limit of quantitation (AUC(O-LOQ)) after ceftiofur hydrochloride administration, was 216+/-28.0 microg x h/mL, compared to 169+/-45.4 microg x h/mL after ceftiofur sodium administration. The calculated time during which plasma concentrations remained above 0.02 microg/mL (t(>0.2)) was 85.3+/-10.6 h for ceftiofur sodium and 77.2+/-10.7 h for ceftiofur hydrochloride. In the 5 mg/kg dosage study, C(max) after administration of ceftiofur sodium was 28.3+/-4.45 microg/mL at 0.33-2 h after injection. After administration of ceftiofur hydrochloride, the C(max) was 29.7+/-6.72 microg/mL at 0.66-2 h after injection. Concentrations of ceftiofur and metabolites 96 h after the injection were 0.274+/-0.0550 microg/mL for ceftiofur hydrochloride and 0.224+/-0.0350 microg/mL for ceftiofur sodium. The mean AUC(O-LOQ) after ceftiofur hydrochloride administration was 382+/-89.8 microg x h/mL compared to 302+/-54.4 microg x h/mL after ceftiofur sodium administration. The t(>0.2) was 78.9+/-9.65 h for ceftiofur sodium and 94.2+/-8.64 h for ceftiofur hydrochloride. Based on the similarity of the pharmacokinetic parameters of the sodium and hydrochloride formulations of ceftiofur, similar therapeutic efficacy can be inferred for the two products.

Evaluation of ceftiofur–PHBV microparticles in rats

“…The C max of DCA obtained in the group treated with ceftiofur–PHBV was 1.9 times lower than the C max (11.8±1.6 μg/mL) described in the study of Brown et al in pigs that received 3 mg/kg weight via im injection 18. Also, the C max of DCA in the group of ceftiofur–PHBV was 1.6 times lower than the C max (10.3±1.2 μg/mL) reported by Goudah in camels treated with 2.2 mg/kg weight of ceftiofur using the same route of administration 31.…”

“…For the elimination half-life (t ½ ), ceftiofur–PHBV showed a longer plasma circulation time than nonencapsulated ceftiofur, and also longer t ½ than others studies in pigs (16.7±2.3 hours) injected with 3 mg/kg weight (im) of ceftiofur, llamas (8.1±1.7 hours) injected with 2.2 mg/kg (im), and alpacas (8.2±1.3 hours) that received doses in the range of 1.30 to 1.51 mg/kg via im injection 18,32. In addition, the sustained release of ceftiofur from ceftiofur–PHBV was longer (17 days) than that of other long-acting drug delivery systems based on liposomes (2 days) and crystalline-free acid sterile suspension (10 days) 33,34.…”

“…Studies in rats, cattle and swine have demonstrated that ceftiofur is metabolized in the liver to desfuroylceftiofur (primary metabolite), which has similar antimicrobial activity because it conserves its β-lactam structure 15–17. Due to the biotransformation of ceftiofur in the liver, ceftiofur cannot be directly measured; however the plasma concentration of ceftiofur can be quantified indirectly as desfuroylceftiofur acetamide after the derivatization process as described in previous reports 16,18…”

Aqueous Suspensions

“…For example, the pharmacokinetic data for both the SC and IM administration illustrate that the availability of the sodium salt of ceftiofur from an aqueous solution is similar to that of the HCl salt from an oil suspension in cattle (Table 8.3 , with the exception of the higher blood plasma maximum concentration for the solution [ 36 ] ). Similar fi ndings of therapeutic equivalence were noted in swine [ 37 ] . This further illustrates the complex interplay of factors at the site of injection including the solubility and the rate of dissolution.…”

Ceftiofur Distribution in Plasma and Tissues Following Subcutaneously Administration in Ducks

“…In the Amazon parrots, ceftiofur was declined to 0.27 µg/g in the plasma by 24 hr post intramuscular administration at the concentration of 10 mg/kg body weight. Brown et al [3] carried out a comparative study of plasma pharmacokinetics of ceftiofur sodium and ceftiofur hydrochloride in pigs after a single intramuscular injection at the dose of 3 mg or 5 mg/body weight, and analyzed these in the plasma with HPLC method. The analytical results showed that the concentration of ceftiofur sodium at 72 hr after the 3 mg injection was 0.27 µg/g, and that at 96 hr after the 5 mg injection was 0.224 µg/g.…”