Comparative Plasma and Interstitial Fluid Pharmacokinetics of Meloxicam, Flunixin, and Ketoprofen in Neonatal Piglets

Mays

Routh

et al. 2020

Preprint

Self Cite

Background: The objective of this study was to compare plasma and urine concentrations of flunixin and meloxicam in pigs, in order to determine urine withdrawal intervals for animals at livestock shows where urine is routinely tested for these drugs. Fourteen Yorkshire/Landrace cross pigs were housed in individual metabolism cages to facilitate complete urine collection. All animals were randomly divided into one of two treatment groups and received either 2.2 mg/kg flunixin or 0.4 mg/kg meloxicam via intramuscular injection. Plasma and urine were collected and analyzed by UPLC-MS/MS. Pigs were humanely euthanized when meloxicam/flunixin could no longer be detected in two consecutive urine samples, and liver and kidneys were collected to quantify any potential residues.Results: Drug levels in urine reached peak concentrations between 4 and 8 h post-dose for both flunixin and meloxicam. Flunixin urine concentrations were higher than maximum levels determined in plasma. Urine concentrations for flunixin and meloxicam were last detected above the limit of quantification (LOQ) at 120 h (0.0005 μg/mL) and 48 h (0.001 μg/mL), respectively. Mean apparent elimination half-life in plasma was 5.00 ± 1.89 h and 3.22 ± 1.52 h for flunixin and meloxicam, respectively. Six of seven pigs had detectable liver concentrations of flunixin (range 0.0001-0.0012 μg/g) following negative urine samples at 96 and 168 h, however all samples at 168 h were below the FDA tolerance level (0.03 μg/g). Meloxicam was detected in a single liver sample at necropsy (0.0054 μg/g) at 72 h but was below the EU MRL (0.065 μg/g) which was used to determine a safety level when FDA tolerance or FSIS testing limits were not established. Urine concentrations did not relate to liver residues at the single slaughter time Conclusions: This data suggests that pigs given a single intramuscular dose of meloxicam at 0.4 mg/kg or flunixin at 2.2 mg/kg are unlikely to have tissue residues above the US FDA tolerance or EU MRL following negative urine testing. This information will assist in generating withdrawal intervals for these NSAIDs for show pigs that might undergo a urine test by the livestock show authorities.

Section: Urinesupporting

confidence: 85%

supporting

confidence: 88%

mentioning

confidence: 99%

See 1 more Smart Citation

Plasma, Urine and Tissue Concentrations of Flunixin and Meloxicam in Pigs

Mays

Routh

et al. 2020

Preprint

Self Cite

“…Following intramuscular administration of 0.4 mg/kg meloxicam, the peak plasma concentration was reached around 0.37 h), which was comparable to previously reported in 8-day-old piglets given a dose of 1 mg/kg (0.50 h (22)), but less than that reported in 5-day-old piglets given 0. Volume of distribution/F in this study for meloxicam (0.41 L/kg) was comparable to that of other studies investigating piglets 5-23 days of age, as well as mature sows, given doses in the range of 0.4-1.0 mg/kg and given via intramuscular or intravenous routes of administration (18,19,22,24,25).…”

Section: Liver and Kidneysupporting

confidence: 85%

“…Only one kidney sample tested positive for unixin (right kidney 0.0002 μg/g). Although there is no FDA tolerance level for kidney, this was far below the FSIS con rmatory limit of detection of 0.0125 μg/g (15) (17,18). Elimination half-life is a hybrid variable and can be altered by ip-op kinetics and changes in drug distribution and clearance.…”

Section: Liver and Kidneymentioning

confidence: 92%

Plasma, Urine and Tissue Concentrations of Flunixin and Meloxicam in Pigs

Mays

Routh

et al. 2020

Preprint

Self Cite

Background: The objective of this study was to determine the renal clearance of flunixin and meloxicam in pigs and compare plasma and urine concentrations and tissue residues of these drugs. Urine clearance is important for livestock show animals where urine is routinely tested for these drugs. Fourteen Yorkshire/Landrace cross pigs were housed in individual metabolism cages to facilitate urine collection. This is a unique feature of this study compared to other reports. Animals into received either 2.2 mg/kg flunixin or 0.4 mg/kg meloxicam via intramuscular injection and samples analyzed by mass spectrometry. Pigs were euthanized when drugs were no longer detected in urine and liver and kidneys were collected to quantify residues.Results: Drug levels in urine reached peak concentrations between 4 and 8 h post-dose for both flunixin and meloxicam. Flunixin urine concentrations were higher than maximum levels in plasma. Urine concentrations for flunixin and meloxicam were last detected above the limit of quantification at 120 h and 48 h, respectively. The renal clearance of flunixin and meloxicam was 4.72 ± 2.98 mL/h/kg and 0.16 ± 0.04 mL/h/kg, respectively. Mean apparent elimination half-life in plasma was 5.00 ± 1.89 h and 3.22 ± 1.52 h for flunixin and meloxicam, respectively. Six of seven pigs had detectable liver concentrations of flunixin (range 0.0001-0.0012 μg/g) following negative urine samples at 96 and 168 h, however all samples at 168 h were below the FDA tolerance level (0.03 μg/g). Meloxicam was detected in a single liver sample (0.0054 μg/g) at 72 h but was below the EU MRL (0.065 μg/g). Conclusions: These data suggest that pigs given a single intramuscular dose of meloxicam at 0.4 mg/kg or flunixin at 2.2 mg/kg are likely to have detectable levels of the parent drug in urine up to 2 days and 5 days, respectively, after the first dose, but unlikely to have tissue residues above the US FDA tolerance or EU MRL following negative urine testing. This information will assist veterinarians in the therapeutic use of these drugs prior to livestock shows and also inform livestock show authorities involved in testing for these substances.

Pharmacokinetic/pharmacodynamic modeling of ketoprofen and flunixin at piglet castration and tail‐docking

Vet Pharm & Therapeutics

Chittenden

Baynes

et al. 2022

Self Cite

This study performed population‐pharmacokinetic/pharmacodynamic (pop‐PK/PD) modeling of ketoprofen and flunixin in piglets undergoing routine castration and tail‐docking, utilizing previously published data. Six‐day‐old male piglets (8/group) received either ketoprofen (3.0 mg/kg) or flunixin (2.2 mg/kg) intramuscularly. Two hours post‐dose, piglets were castrated and tail docked. Inhibitory indirect response models were developed utilizing plasma cortisol or interstitial fluid prostaglandin E2 (PGE2) concentration data. Plasma IC50 for ketoprofen utilizing PGE2 as a biomarker was 1.2 μg/ml, and ED50 for was 5.83 mg/kg. The ED50 calculated using cortisol was 4.36 mg/kg; however, the IC50 was high, at 2.56 μg/ml. A large degree of inter‐individual variability (124.08%) was also associated with the cortisol IC50 following ketoprofen administration. IC50 for flunixin utilizing cortisol as a biomarker was 0.06 μg/ml, and ED50 was 0.51 mg/kg. The results show that the currently marketed doses of ketoprofen (3.0 mg/kg) and flunixin (2.2 mg/kg) correspond to drug responses of 33.97% (ketoprofen‐PGE2), 40.75% (ketoprofen‐cortisol), and 81.05% (flunixin‐cortisol) of the maximal possible responses. Given this information, flunixin may be the best NSAID to use in mitigating castration and tail‐docking pain at the current label dose.