Estimation of tulathromycin depletion in plasma and milk after subcutaneous injection in lactating goats using a nonlinear mixed-effects pharmacokinetic modeling approachReport as inadecuate




Estimation of tulathromycin depletion in plasma and milk after subcutaneous injection in lactating goats using a nonlinear mixed-effects pharmacokinetic modeling approach - Download this document for free, or read online. Document in PDF available to download.

BMC Veterinary Research

, 12:258

Pharmacology and toxicology

Abstract

BackgroundExtra-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.

ResultsAll 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.

ConclusionsThe 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.

KeywordsTulathromycin Withdrawal time Goat Food safety Nonlinear mixed-effects NLME pharmacokinetic modeling AbbreviationsCIConfidence interval

IMIntramuscular

IVIntravenous

LC-MSLiquid chromatography mass spectrometry

LODLimit of detection

LOQLimit of quantification

MICMinimal inhibitory concentration

NLME-PKNonlinear mixed-effects pharmacokinetic

PBPKPhysiologically based pharmacokinetic

SCSubcutaneous

SRMSelected reaction monitoring

Electronic supplementary materialThe online version of this article doi:10.1186-s12917-016-0884-4 contains supplementary material, which is available to authorized users.

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Author: Zhoumeng Lin - Matthew Cuneo - Joan D. Rowe - Mengjie Li - Lisa A. Tell - Shayna Allison - Jan Carlson - Jim E. Riviere

Source: https://link.springer.com/







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