Pharmacokinetics of Intravenous, Intramuscular, Oral, and Transdermal Administration of Flunixin Meglumine in Pre-wean Piglets

Abstract

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.

Pharmacokinetics of transdermal flunixin meglumine and effects on biomarkers of inflammation in horses

“…The difference in the terminal half‐life between previous reports and the current study suggests flip‐flop kinetics following transdermal administration, a phenomenon whereby the rate of absorption is slower compared with the rate of elimination. Flip‐flop kinetics has been suggested following transdermal administration of flunixin meglumine in pre‐wean piglets as well (Kittrell et al, 2020).…”

“…As transdermal administration is non‐invasive, the purported benefits of this product include reduced handling of animals and ease of administration (Banamine Transdermal® label). The pharmacokinetics and potential therapeutic uses of transdermal administration have been described in a number of species, including cattle, goats, and pigs (Cramer et al, 2019; Kittrell et al, 2020; Kleinhenz et al, 2016; Reppert et al, 2019). While the transdermal formulation is not approved for use in horses and to the best of the authors’ knowledge, there are no published reports describing its use, and the convenience of this route of administration may be appealing to horse owners.…”

“…Flip-flop kinetics has been suggested following transdermal administration of flunixin meglumine in pre-wean piglets as well(Kittrell et al, 2020).Serum concentrations of both the parent compound and metabolite were above the LOD of the analytical assay at the last time pointmeasured. Additionally, both flunixin and 5-OH flunixin were detectable in urine for up to 96 h post-administration in all horses studied.…”

Pharmacokinetic Evaluation of a Novel Transdermal Ketoprofen Formulation in Healthy Dogs

“…Each NSAID was initially screened for its solubility in a large range of vehicles and penetration enhancers ( Table S1 ). Vehicle combinations dissolving ≥5% [ 30 ] of drugs were further modified to determine which excipients, and in which range of concentrations or proportions, dissolved a greater amount of each NSAID. Most of the excipients were mixed with water as a co-solvent and were tested for in vitro drug permeation at a 10% w/v concentration ( Tables S2 and S3 ).…”

“…Only a few studies have reported successful transdermal delivery of NSAIDs in animals, including ketoprofen in cattle [ 26 ] and pigs [ 27 ], and flunixin meglumine in horses [ 28 ], goats [ 29 ], and piglets [ 30 ]. Some studies targeted local penetration only, including naproxen [ 31 ], methyl salicylate [ 32 ], meloxicam [ 33 ], and celecoxib [ 34 ].…”