title: Estimation of tulathromycin depletion in plasma and milk after subcutaneous injection in lactating goats using a nonlinear mixed-effects pharmacokinetic modeling approach.
abstract: BACKGROUND
  Extra-label use of tulathromycin in lactating goats is common and may cause violative residues in milk. The objective of this study was to develop a nonlinear mixed-effects pharmacokinetic (NLME-PK) model to estimate tulathromycin depletion in plasma and milk of lactating goats. Eight lactating goats received two subcutaneous injections of 2.5 mg/kg tulathromycin 7 days apart; blood and milk samples were analyzed for concentrations of tulathromycin and the common fragment of tulathromycin (i.e., the marker residue CP-60,300), respectively, using liquid chromatography mass spectrometry. Based on these new data and related literature data, a NLME-PK compartmental model with first-order absorption and elimination was used to model plasma concentrations and cumulative excreted amount in milk. Monte Carlo simulations with 100 replicates were performed to predict the time when the upper limit of the 95% confidence interval of milk concentrations was below the tolerance.
  
  
  RESULTS
  All animals were healthy throughout the study with normal appetite and milk production levels, and with mild-moderate injection-site reactions that diminished by the end of the study. The measured data showed that milk concentrations of the marker residue of tulathromycin were below the limit of detection (LOD = 1.8 ng/ml) 39 days after the second injection. A 2-compartment model with milk as an excretory compartment best described tulathromycin plasma and CP-60,300 milk pharmacokinetic data. The model-predicted data correlated with the measured data very well. The NLME-PK model estimated that tulathromycin plasma concentrations were below LOD (1.2 ng/ml) 43 days after a single injection, and 62 days after the second injection with a 95% confidence. These estimated times are much longer than the current meat withdrawal time recommendation of 18 days for tulathromycin in non-lactating cattle.
  
  
  CONCLUSIONS
  The results suggest that twice subcutaneous injections of 2.5 mg/kg tulathromycin are a clinically safe extra-label alternative approach for treating pulmonary infections in lactating goats, but a prolonged withdrawal time of at least 39 days after the second injection should be considered to prevent violative residues in milk and any dairy goat being used for meat should have an extended meat withdrawal time.
authors.affiliation: Institute of Computational Comparative Medicine (ICCM), Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, 1800 Denison Avenue, P200 Mosier Hall, Manhattan, KS, 66506-5802, USA.
authors.forename: Zhoumeng
authors.initials: Z
authors.lastname: Lin
authors.affiliation: Department of Population, Health and Reproduction, College of Agricultural and Environmental Sciences, University of California, Davis, CA, 95616, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Cuneo
authors.affiliation: Department of Population, Health and Reproduction, College of Agricultural and Environmental Sciences, University of California, Davis, CA, 95616, USA.
authors.forename: Joan D
authors.initials: JD
authors.lastname: Rowe
authors.affiliation: Institute of Computational Comparative Medicine (ICCM), Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, 1800 Denison Avenue, P200 Mosier Hall, Manhattan, KS, 66506-5802, USA.|Present address: Department of Pharmaceutical Science, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73117, USA.
authors.forename: Mengjie
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Medicine and Epidemiology, College of Agricultural and Environmental Sciences, University of California, Davis, CA, 95616, USA.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Tell
authors.affiliation: School of Veterinary Medicine, and Department of Animal Science, College of Agricultural and Environmental Sciences, University of California, Davis, CA, 95616, USA.
authors.forename: Shayna
authors.initials: S
authors.lastname: Allison
authors.affiliation: School of Veterinary Medicine, and Department of Animal Science, College of Agricultural and Environmental Sciences, University of California, Davis, CA, 95616, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Carlson
authors.affiliation: Institute of Computational Comparative Medicine (ICCM), Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, 1800 Denison Avenue, P200 Mosier Hall, Manhattan, KS, 66506-5802, USA.
authors.forename: Jim E
authors.initials: JE
authors.lastname: Riviere
authors.affiliation: Institute of Computational Comparative Medicine (ICCM), Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, 1800 Denison Avenue, P200 Mosier Hall, Manhattan, KS, 66506-5802, USA. rgehring@ksu.edu.
authors.forename: Ronette
authors.identifier: http://orcid.org/0000-0002-1329-201X
authors.initials: R
authors.lastname: Gehring
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D004187:Disaccharides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006041:Goats / Q000378:metabolism*; D006571:Heterocyclic Compounds / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D007279:Injections, Subcutaneous; D057230:Limit of Detection; D008892:Milk / Q000737:chemistry*; D009010:Monte Carlo Method; D017711:Nonlinear Dynamics; D018942:Macrolides
chemical_list: D000900:Anti-Bacterial Agents; D004187:Disaccharides; D006571:Heterocyclic Compounds; C485204:tulathromycin; D018942:Macrolides
keywords: Food safety; Goat; Nonlinear mixed-effects (NLME) pharmacokinetic modeling; Tulathromycin; Withdrawal time