Pharmacokinetic Modeling of Ceftiofur Sodium Using Non-linear Mixed-Effects in Healthy Beagle Dogs

摘要

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, nonlinear 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 hours 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 approximately 30 hours.