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

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

Bioavailability of suppository acetaminophen in healthy and hospitalized ill dogs

“…The nonlinear mixed‐effects approach as implemented in Phoenix NLME™ (version 7.0, Certara USA, Inc., Cary, NC) was used to fit the plasma acetaminophen concentration data to a compartmental pharmacokinetic model for both the healthy ( n = 6) and hospitalized ( n = 20) dogs (Li et al., ; Lin et al., ; Mould & Upton, ; Upton & Mould, ). In brief, the extended least‐squares, first‐order conditional estimation (FOCE‐ELS) algorithm with interaction was used to fit the data to the model and to calculate the population pharmacokinetic parameters.…”

Mathematical modeling and simulation in animal health. Part III: Using nonlinear mixed‐effects to characterize and quantify variability in drug pharmacokinetics

“…Over the past 15 years, several peer‐reviewed NLME analyses in veterinary pharmacology have been published. The most recent examples include the study of topiramate in epileptic dogs (Vuu et al., ); nonsteroidal anti‐inflammatory drug (NSAIDs) in dogs and cats with osteoarthritis (Cox, Liao, Payne‐Johnson, Zielinski, & Stegemann, ; Fink et al., ; Pelligand, Soubret, King, Elliott, & Mochel, ; Silber et al., ); tobramycin in horses (Haritova, Bakalov, Hubenov, & Lashev, ); valnemulin and cefquinome in pigs (Zhao et al., , ); tulathromycin in lactating goats (Lin, Cuneo et al., ; Lin, Gehring et al., ); and penicillin G in cattle and swine (Li et al., ).…”

“…It proved to be particularly useful in the context of large interindividual variability, or where drug PK could be affected by the disease process or the drug itself (Sheiner, 1985). Because this modeling approach is amenable to sparsely sampled blood or tissue samples (Sheiner & Beal, 1983), it was later recognized to be of value in veterinary pharmacology to explore the impact of covariates such as age, sex, and disease status on drug PK (Martin-Jimenez & Riviere, 1998 (Haritova, Bakalov, Hubenov, & Lashev, 2012); valnemulin and cefquinome in pigs (Zhao et al, 2013(Zhao et al, , 2014; tulathromycin in lactating goats (Lin, Cuneo et al, 2016;; and penicillin G in cattle and swine (Li et al, 2014).…”

“…. (2014),Kissell et al (2015),Shelver et al (2016),Sidhu et al (2017) andSilber et al (2010) LactationLin, Cuneo et al (2016) and Interoccasion variability Time-dependent physiological changesLee et al (2006) andKonturek et al (2011) Chronobiology andMochel et al (2014 Loc(ation (owner's home vs. veterinary hospital) Whittem et al(2000)…”

Extralabel drug use in small ruminants

“…Like all macrolides, tulathromycin persists for an extended period in the milk of treated animals. 89,90 For the lactating goats of 1 study, 89 tulathromycin residues were still detectable in milk 45 days after administration of a single dose of the drug (2.5 mg/kg, SC). Therefore, administration of tulathromycin to lactating animals is not recommended.…”