Pharmacokinetic Modeling of Ceftiofur Sodium Using Non-linear Mixed-Effects in Healthy Beagle Dogs
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-lin...
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| Format: | Article |
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Frontiers Media S.A.
2019-10-01
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| Series: | Frontiers in Veterinary Science |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fvets.2019.00363/full |
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| author | Jianzhong Wang Jianzhong Wang Jianzhong Wang Benjamin K. Schneider Jiao Xue Jiao Xue Pan Sun Pan Sun Jicheng Qiu Jicheng Qiu Jonathan P. Mochel Xingyuan Cao Xingyuan Cao Xingyuan Cao |
| author_facet | Jianzhong Wang Jianzhong Wang Jianzhong Wang Benjamin K. Schneider Jiao Xue Jiao Xue Pan Sun Pan Sun Jicheng Qiu Jicheng Qiu Jonathan P. Mochel Xingyuan Cao Xingyuan Cao Xingyuan Cao |
| author_sort | Jianzhong Wang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T14:37:52Z |
| format | Article |
| id | doaj.art-a2c1d0ca9c4e42bcbeb11728f5dffb51 |
| institution | Directory Open Access Journal |
| issn | 2297-1769 |
| language | English |
| last_indexed | 2024-12-13T14:37:52Z |
| publishDate | 2019-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Veterinary Science |
| spelling | doaj.art-a2c1d0ca9c4e42bcbeb11728f5dffb512022-12-21T23:41:41ZengFrontiers Media S.A.Frontiers in Veterinary Science2297-17692019-10-01610.3389/fvets.2019.00363488309Pharmacokinetic Modeling of Ceftiofur Sodium Using Non-linear Mixed-Effects in Healthy Beagle DogsJianzhong Wang0Jianzhong Wang1Jianzhong Wang2Benjamin K. Schneider3Jiao Xue4Jiao Xue5Pan Sun6Pan Sun7Jicheng Qiu8Jicheng Qiu9Jonathan P. Mochel10Xingyuan Cao11Xingyuan Cao12Xingyuan Cao13Department of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Beijing, ChinaLaboratory of Quality & Safety Risk Assessment for Animal Products on Chemical Hazards (Beijing), Ministry of Agriculture and Rural Affairs, Beijing, ChinaBiomedical Sciences, SMART Pharmacology, College of Veterinary Medicine, Iowa State University, Ames, IA, United StatesBiomedical Sciences, SMART Pharmacology, College of Veterinary Medicine, Iowa State University, Ames, IA, United StatesDepartment of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Beijing, ChinaLaboratory of Quality & Safety Risk Assessment for Animal Products on Chemical Hazards (Beijing), Ministry of Agriculture and Rural Affairs, Beijing, ChinaDepartment of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Beijing, ChinaLaboratory of Quality & Safety Risk Assessment for Animal Products on Chemical Hazards (Beijing), Ministry of Agriculture and Rural Affairs, Beijing, ChinaDepartment of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Beijing, ChinaLaboratory of Quality & Safety Risk Assessment for Animal Products on Chemical Hazards (Beijing), Ministry of Agriculture and Rural Affairs, Beijing, ChinaBiomedical Sciences, SMART Pharmacology, College of Veterinary Medicine, Iowa State University, Ames, IA, United StatesDepartment of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Beijing, ChinaLaboratory of Quality & Safety Risk Assessment for Animal Products on Chemical Hazards (Beijing), Ministry of Agriculture and Rural Affairs, Beijing, ChinaLaboratory of Detection for Veterinary Drug Residues and Illegal Additives, Ministry of Agriculture and Rural Affairs, Beijing, ChinaCeftiofur (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.https://www.frontiersin.org/article/10.3389/fvets.2019.00363/fullceftiofur sodiumpharmacokineticsNLMEmonte carlo simulationsdogs |
| spellingShingle | Jianzhong Wang Jianzhong Wang Jianzhong Wang Benjamin K. Schneider Jiao Xue Jiao Xue Pan Sun Pan Sun Jicheng Qiu Jicheng Qiu Jonathan P. Mochel Xingyuan Cao Xingyuan Cao Xingyuan Cao Pharmacokinetic Modeling of Ceftiofur Sodium Using Non-linear Mixed-Effects in Healthy Beagle Dogs Frontiers in Veterinary Science ceftiofur sodium pharmacokinetics NLME monte carlo simulations dogs |
| title | Pharmacokinetic Modeling of Ceftiofur Sodium Using Non-linear Mixed-Effects in Healthy Beagle Dogs |
| title_full | Pharmacokinetic Modeling of Ceftiofur Sodium Using Non-linear Mixed-Effects in Healthy Beagle Dogs |
| title_fullStr | Pharmacokinetic Modeling of Ceftiofur Sodium Using Non-linear Mixed-Effects in Healthy Beagle Dogs |
| title_full_unstemmed | Pharmacokinetic Modeling of Ceftiofur Sodium Using Non-linear Mixed-Effects in Healthy Beagle Dogs |
| title_short | Pharmacokinetic Modeling of Ceftiofur Sodium Using Non-linear Mixed-Effects in Healthy Beagle Dogs |
| title_sort | pharmacokinetic modeling of ceftiofur sodium using non linear mixed effects in healthy beagle dogs |
| topic | ceftiofur sodium pharmacokinetics NLME monte carlo simulations dogs |
| url | https://www.frontiersin.org/article/10.3389/fvets.2019.00363/full |
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