Abstract
Ceftiofur (CEF) sodium is a third-generation broad-spectrum cephalosporin commonly used in an extra-label manner in dogs for the treatment of respiratory and urinary system infections. To contribute to the literature supporting CEF use in companion animals, we have developed a compartmental, non-linear mixed-effects (NLME) model of CEF pharmacokinetics in dogs (PK). We then used the mathematical model to predict (via Monte Carlo simulation) the duration of time for which plasma concentrations of CEF and its pharmacologically active metabolites remained above minimum inhibitory concentrations (respiratory tract Escherichia coli spp.). Twelve healthy beagle dogs were administered either 2.2 mg/kg ceftiofur-sodium (CEF-Na) intravenously (I.V) or 2.2 mg/kg CEF-Na subcutaneously (S.C). Plasma samples were collected over a period of 72 h post-administration. To produce a measurement of total CEF, both CEF and CEF metabolites were derivatized into desfuroylceftiofur acetamide (DCA) before analysis by UPLC-MS/MS. No adverse effects were reported after I.V or S.C dosing. The NLME PK models were parameterized using the stochastic approximation expectation maximization algorithm as implemented in Monolix 2018R2. A two-compartment mamillary model with first-order elimination and first-order S.C absorption best described the available kinetic data. Final parameter estimates indicate that CEF has a low systemic clearance (0.25 L/h/kg) associated with a low global extraction ratio E = 0.02) and a moderate volume of distribution (2.97 L/kg) in dogs. The absolute bioavailability after S.C administration was high (93.7%). Gender was determined to be a significant covariate in explaining the variability of S.C absorption. Our simulations predicted that a dose of 2.2 mg/kg CEF-Na S.C would produce median plasma concentrations of CEF of at least 0.5 μg/mL (MIC50) for ~30 h.
Highlights
Ceftiofur sodium (CEF-Na) is a third-generation broad-spectrum cephalosporin (β-lactam antibiotic) which is effective against Gram-positive, Gram-negative, anaerobic, and β-lactamase producing bacteria [1]
After model building and validation, the resulting fit was used to predict the duration of time for which plasma concentrations of CEF and its pharmacologically active metabolites remained above minimum inhibitory concentrations (MIC50, MIC90) for respiratory tract Escherichia coli spp.— the most common respiratory and urinary tract pathogens in dogs
A two-compartment mammillary PK model with first-order elimination and first-order absorption for the S.C route, was found to best fit the pharmacokinetics of CEF equivalents in plasma based on standard goodness-of-fit diagnostic plots, precision of parameter estimates (RSE), as well as comparison of Bayesian information criteria (BIC) between competing structural models (Figures 1–3) [31]
Summary
Ceftiofur sodium (CEF-Na) is a third-generation broad-spectrum cephalosporin (β-lactam antibiotic) which is effective against Gram-positive, Gram-negative, anaerobic, and β-lactamase producing bacteria [1]. The metabolism of ceftiofur is similar in rats [15], cattle [15], swine [16], horses [17], and dogs [18] and is characterized by rapid cleavage of the thioester bond to the active metabolite desfuroylceftiofur (DFC) and furoic acid after parenteral administration. Free DFC (which contains an intact β-lactam ring) is the primary microbiologically active metabolite of ceftiofur [6]. It is further metabolized to disulfides and bound to macromolecules in plasma and tissues which are DFC-glutathione disulfide, DFCcysteine disulfide, 3,3-DFC-disulfide (DFC-dimer), and DFC-protein [19]
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