Title
Pharmacokinetic Modeling of Ceftiofur Sodium Using Nonlinear Mixed-Effects in Healthy Beagle Dogs
Campus Units
Biomedical Sciences, Veterinary Diagnostic and Production Animal Medicine
Document Type
Article
Publication Version
Submitted Manuscript
Publication Date
7-28-2019
Journal or Book Title
Preprints
DOI
10.20944/preprints201907.0322.v1
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, 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 mammillary 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.
Copyright Owner
The Authors
Copyright Date
2019
Language
en
File Format
application/pdf
Recommended Citation
Wang, Jianzhong; Schneider, Benjamin K.; Xue, Jiao; Sun, Pan; Qiu, Jicheng; Mochel, Jonathan P.; and Cao, Xingyuan, "Pharmacokinetic Modeling of Ceftiofur Sodium Using Nonlinear Mixed-Effects in Healthy Beagle Dogs" (2019). Biomedical Sciences Publications. 73.
https://lib.dr.iastate.edu/bms_pubs/73
Included in
Small or Companion Animal Medicine Commons, Veterinary Toxicology and Pharmacology Commons
Comments
This is a pre-print of the article Wang, Jianzhong, Benjamin Schneider, Jiao Xue, Pan Sun, Jicheng Qiu, Jonathan Mochel, and Xingyuan Cao. "Pharmacokinetic Modeling of Ceftiofur Sodium Using Nonlinear Mixed-Effects in Healthy Beagle Dogs." (2019). Preprints (2019): 2019070322. DOI: 10.20944/preprints201907.0322.v1. Posted with permission.