title: Development of a physiologically based pharmacokinetic model to predict tulathromycin distribution in goats.
abstract: Physiologically based pharmacokinetic (PBPK) models, which incorporate species- and chemical-specific parameters, could be useful tools for extrapolating withdrawal times for drugs across species and doses. The objective of this research was to develop a PBPK model for goats to simulate the pharmacokinetics of tulathromycin, a macrolide antibiotic effective for treating respiratory infections. Model compartments included plasma, lung, liver, muscle, adipose tissue, kidney, and remaining poorly and richly perfused tissues. Tulathromycin was assumed to be 50% protein bound in plasma with first-order clearance. Literature values were compiled for physiological parameters, partition coefficients were estimated from tissue:plasma ratios of AUC, and the remaining model parameters were estimated by comparison against the experimental data. Three separate model structures were compared with plasma and tissue concentrations of tulathromycin in market age goats administered 2.5 mg/kg tulathromycin subcutaneously. The best simulation was achieved with a diffusion-limited PBPK model and absorption from a two-compartment injection site, which allowed for low persistent concentrations at the injection site and slower depletion in the tissues than the plasma as observed with the experimental data. The model with age-appropriate physiological parameters also predicted plasma concentrations in juvenile goats administered tulathromycin subcutaneously. The developed model and compilation of physiological parameters for goats provide initial tools that can be used as a basis for predicting withdrawal times of drugs in this minor species.
authors.affiliation: Center for Chemical Toxicology Research and Pharmacokinetics, Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27709, USA. Teresa_leavens@ncsu.edu
authors.forename: T L
authors.initials: TL
authors.lastname: Leavens
authors.forename: L A
authors.initials: LA
authors.lastname: Tell
authors.forename: K A
authors.initials: KA
authors.lastname: Clothier
authors.forename: R W
authors.initials: RW
authors.lastname: Griffith
authors.forename: R E
authors.initials: RE
authors.lastname: Baynes
authors.forename: J E
authors.initials: JE
authors.lastname: Riviere
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics*; D003198:Computer Simulation; D004187:Disaccharides / Q000097:blood / Q000493:pharmacokinetics*; D006041:Goats / Q000097:blood / Q000378:metabolism*; D006571:Heterocyclic Compounds / Q000097:blood / Q000493:pharmacokinetics*; D008954:Models, Biological; D012680:Sensitivity and Specificity; D012984:Software; D014018:Tissue Distribution; D018942:Macrolides
chemical_list: D000900:Anti-Bacterial Agents; D004187:Disaccharides; D006571:Heterocyclic Compounds; C485204:tulathromycin; D018942:Macrolides