Date of Award
Doctor of Philosophy
Veterinary Diagnostic and Production Animal Medicine
Population Sciences in Animal Health
With the transdermal (TD) application of flunixin meglumine (FM) now approved for pain control in cattle, Animal Medicinal Drug Use Clarification Act (AMDUCA) algorithms suggest that the product should be considered when treating pain in other food animal species. The use of non-steroidal anti-inflammatory products may reduce the pain associated with castration and tail-docking during piglet processing. Confirming that FM reaches useful serum levels would allow development of dose regimens for pre-wean piglets.
The first objective of this dissertation was to establish the pharmacokinetics (PK) of intravenous (IV), intramuscular (IM), oral (PO), and TD administration of FM in pre-wean piglets, and evaluate the ability of TD FM to reach therapeutic levels that mitigate pain in other species and adult pigs. In order to measure the PK in pre-wean piglets, FM was administered to 39 piglets, 5-10 days of age, weighing less than 10 pounds. The study was divided into two phases: Phase I evaluated the PK of PO, TD and IM administration and phase II evaluated the bioavailability of TD FM using a crossover study design of IV and TD administration. The dose for IV and IM was 2.2 mg/kg while the PO and TD dose was 3.3 mg/kg. Blood samples were collected from the jugular vein at 27 consecutive time points from 0-9 days post-administration. Plasma FM concentrations were determined using ultra high-performance liquid chromatography and analyzed with noncompartmental analysis and nonlinear mixed-effect modeling techniques. The median (± standard deviation, sd) C0 for IV was 11653.3 μg/L (±5491.69) and CMAX for the IM, PO, and TD routes of administration were 6543 μg/L (±1463.3), 4883 μg/L (±1715.91), and 31.5 μg/L (±23.79), respectively. The median AUC∞ (± sd) were estimated at 1,339,300 (±1,017,190) min*µg/L, 1652770 (±644053) min*µg/L, 1971720 (±657684) min*µg/L, and 125218 (±77262.5) min*µg/L for IV, IM, PO, and TD, respectively. The time points of peak FM concentrations (Tmax) were estimated at 30 min, 1 hr, and 24 hrs for IM, PO, and TD, respectively. The absolute bioavailability of PO FM was estimated at greater than 99%, while the bioavailability of TD FM was estimated to be low, 7.86%.
An additional objective was to use covariates of age and weight and a collection of data from previous research to establish PK in various production classes of swine. A literature review was performed using PubMed and American Association of Swine Veterinarians with the following search terms: swine OR pig* OR sow* OR gilt* OR boar* OR hog* AND flunixin. Original research was comprehensively analyzed for inclusion of swine-specific FM PK data. Authors were contacted for release of data. Data from four studies, including one study from this dissertation, were pooled for nonlinear mixed-effects modeling. The population parameters were estimated at 2.58 L/hour, 3.36 L, 13.2 L for the clearance, central volume, and peripheral volume, respectively and absolute bioavailability was estimated at 44% for IM, 4.26% for PO, and 4.67% for TD administration. Body weight, log transform of body weight, and IM study occasion were included as covariates in the model, at a threshold of p < 0.05. The study provides the first comprehensive characterization of pooled population PK of FM across a broad range of swine production classes.
Overall, this dissertation establishes the low bioavailability of TD bioavailability, and therefore is not an option for pain control in swine.
Kittrell, Heather, "An investigation of the pharmacokinetics of flunixin meglumine in swine using noncompartmental analysis and nonlinear mixed-effects modeling: An emphasis on pre-wean piglets" (2020). Graduate Theses and Dissertations. 18037.