This study describes the pharmacokinetics of topical and intravenous (IV) flunixin meglumine in Holstein calves. Eight male Holsteins calves, aged 6 to 8 weeks, were administered flunixin at a dose of 2.2 mg/kg intravenously. Following a 10-day washout period, calves were dosed with flunixin at 3.33 mg/kg topically (transdermal). Blood samples were collected at predetermined times from 0 to 48 h for the intravenous portions and 0 to 72 h following topical dosing. Plasma drug concentrations were determined using liquid chromatography with mass spectroscopy. Pharmacokinetic analysis was completed using noncompartmental methods. The mean bioavailability of topical flunixin was calculated to be 48%. The mean AUC for flunixin was determined to be 13.9 h × ug/mL for IV administration and 10.1 h × ug/mL for topical administration. The mean half-life for topical flunixin was 6.42 h and 4.99 h for the intravenous route. The C following topical application of flunixin was 1.17 μg/mL. The time to maximum concentration was 2.14 h. Mean residence time (MRT) following IV injection was 4.38 h and 8.36 h after topical administration. In conclusion, flunixin when administered as a topical preparation is rapidly absorbed and has longer half-life compared to IV administration.

OBJECTIVE To determine the effect of age on the pharmacokinetics and pharmacodynamics of flunixin meglumine following IV and transdermal administration to calves. ANIMALS 8 healthy weaned Holstein bull calves. PROCEDURES At 2 months of age, all calves received an injectable solution of flunixin (2.2 mg/kg, IV); then, after a 10-day washout period, calves received a topical formulation of flunixin (3.33 mg/kg, transdermally). Blood samples were collected at predetermined times before and for 48 and 72 hours, respectively, after IV and transdermal administration. At 8 months of age, the experimental protocol was repeated except calves received flunixin by the transdermal route first. Plasma flunixin concentrations were determined by liquid chromatography-tandem mass spectroscopy. For each administration route, pharmacokinetic parameters were determined by noncompartmental methods and compared between the 2 ages. Plasma prostaglandin (PG) E concentration was determined with an ELISA. The effect of age on the percentage change in PGE concentration was assessed with repeated-measures analysis. The half maximal inhibitory concentration of flunixin on PGE concentration was determined by nonlinear regression. RESULTS Following IV administration, the mean half-life, area under the plasma concentration-time curve, and residence time were lower and the mean clearance was higher for calves at 8 months of age than at 2 months of age. Following transdermal administration, the mean maximum plasma drug concentration was lower and the mean absorption time and residence time were higher for calves at 8 months of age than at 2 months of age. The half maximal inhibitory concentration of flunixin on PGE concentration at 8 months of age was significantly higher than at 2 months of age. Age was not associated with the percentage change in PGE concentration following IV or transdermal flunixin administration. CONCLUSIONS AND CLINICAL RELEVANCE In calves, the clearance of flunixin at 2 months of age was slower than that at 8 months of age following IV administration. Flunixin administration to calves may require age-related adjustments to the dose and dosing interval and an extended withdrawal interval.

The objectives of this study were to determine the concentration of tylvalosin (TVN) and its metabolite, 3-O-acetyltylosin (3AT) in the synovial fluid of growing pigs when administered as a single bolus by oral gavage at target doses of 50 mg/kg (Trial 1) and 5 mg/kg (Trial 2). TVN is a water soluble macrolide antimicrobial used in swine production. The stability of the drug in synovial fluid samples stored at -70 °C up to 28 days was also evaluated in Trial 2. In Trial 1, eight pigs were randomly assigned to one of eight time points for euthanasia and synovial fluid collection: 0, 1, 2, 3, 4, 6, 9, 12 h postgavage. For Trial 2, 24 pigs were randomly allocated to one terminal collection time point at 0, 2, 4, 6, 8 or 10 h postgavage. Synovial fluid was analyzed to determine TVN and 3AT concentrations. TVN and 3AT were detected in Trial 1 at all time points, except 0 h. At 2 h postgavage for trial 2, the mean concentrations peaked at 31.17 ng/mL (95% CI: 18.62-52.16) for TVN and at 58.82 ng/mL (95% CI: 35.14-98.46) for 3AT. Storage duration did not impact TVN or 3AT concentrations (P-value 0.9732).

Castration and tail-docking of pre-wean piglets are common procedures that are known to induce pain and would benefit from pain mitigation. Flunixin meglumine (FM) is a non-steroidal anti-inflammatory drug currently approved in the United States for pyrexia in swine and lameness pain in cattle. The objective of this study was to establish the pharmacokinetic (PK) parameters resulting from intravenous (IV), intramuscular (IM), oral (PO) and transdermal (TD) administration of FM in pre-wean piglets. FM was administered to thirty-nine pre-wean piglets at a target dose of 2.2 mg/kg for IV and IM and 3.3 mg/kg for PO and TD route. Plasma was collected at twenty-seven time points from 0 to 9 days after FM administration and concentrations were determined using ultra-high performance liquid chromatography coupled with mass spectrometry (UPLC-MS). Pharmacokinetic data were analyzed using noncompartmental analysis (NCA) methods and nonlinear mixed-effects (NLME). Initial plasma concentration for IV (C 0) 11,653 µg/L and mean peak plasma concentrations (C max) 6,543 µg/L (IM), 4,883 µg/L (PO), and 31.5 µg/L (TD) were measured. The time points of peak FM concentrations (t max) were estimated 30 min, 1 h, and 24 h for IM, PO, and TD, respectively. The bioavailability (F) of PO and IM FM was estimated at >99%, while the bioavailability of TD FM was estimated to be 7.8%. The reported C max of FM after IM and PO administration is consistent with therapeutic concentration ranges that mitigate pain in other species and adult pigs. However, the low estimated concentration of FM after TD dosing is not expected to mitigate pain in pre-wean piglets. The low F of TD FM suggests that expanding the surface area of application is unlikely to be sufficient to establish an effective TD dose for pain, while the high bioavailability for PO FM should allow for an effective dose regimen to be established.

Tylvalosin (TVN) is a water soluble macrolide used in swine production to treat enteric, respiratory, and arthritic pathogens. There is limited data on its distribution to synovial fluid beyond gavage studies, which do not represent field conditions. This study measured water disappearance, TVN concentration in the medicated water, daily dose, and concentrations of TVN and 3-O-acetyltylosin (3AT) in the synovial fluid and plasma of treated pigs over the administration period. The study emphasized understanding variation in tissue TVN concentrations within the context of a field setting. Sixty finisher pigs were housed individually with individual waterers. Six pigs were randomly allocated to the following time points for sample collection: 0, 48, 60, 72, 84, 96, 102, 108, 114, and 120 hr on medication. TVN was administered daily in the water for 5 days. Water disappearance and medicated water concentration were measured daily. At each time point, six pigs were euthanized and plasma and synovial fluid were collected for analysis. Median TVN synovial fluid concentrations ranged between <1 ng/ml (hour 0) to 3.6 ng/ml (hour 84). There was substantial variation between individual pigs for water disappearance (mean 4.36L and range 0-7.84). Median TVN water concentration was 59 ppm (range 38-75 ppm).