Pharmacokinetic parameters and estimated milk withdrawal intervals for domestic goats (Capra aegagrus hircus) after administration of single and multiple intravenous and subcutaneous doses of flunixin meglumine

Authors: SMITH, JOE - University Of California, Davis; MARMULAK, TARA - University Of California, Davis; ANGELOS, JOHN - University Of California, Davis; LIN, ZHOUMENG - Kansas State University; ROWE, JOAN - University Of California, Davis; CARLSON, JAN - University Of California, Davis; Shelver, Weilin; LEE, ELIZABETH - University Of California, Davis; TELL, LISA - University Of California, Davis

Submitted to: Frontiers in Veterinary Science
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/31/2020
Publication Date: 5/19/2020
Citation: Smith, J.S., Marmulak, T.L., Angelos, J.A., Lin, Z., Rowe, J.D., Carlson, J.L., Shelver, W.L., Lee, E.A., Tell, L.A. 2020. Pharmacokinetic parameters and estimated milk withdrawal intervals for domestic goats (Capra aegagrus hircus) after administration of single and multiple intravenous and subcutaneous doses of flunixin meglumine. Frontiers in Veterinary Science. 7:213. https://doi.org/10.3389/fvets.2020.00213.
DOI: https://doi.org/10.3389/fvets.2020.00213

Interpretive Summary: Non-steroidal anti-inflammatory drugs (NSAIDs) are currently not approved for use in goats to treat inflammatory conditions such as mastitis. Because goats are a food and milk animal of growing importance in the United States, veterinarians are often called to treat inflammatory disease in goats. In the absence of approved animal drugs, veterinarians typically use flunixin, a NSAID approved for use in cattle in an extra-label manner to treat goats. Extra-label flunixin use, however, requires veterinarians to ensure that flunixin residues will not be present in milk or meat used for human food. Such data, however, do not exist. This study was conducted to determine the length of time flunixin residues are present in blood and milk of goats treated with flunixin by either subcutaneous (under the skin) or intravenous (within a vein) administration. From these data pre-harvest withdrawal times were calculated. Veterinarians will use the calculated withdrawal periods to ensure that flunixin residues do not enter the human food supply.

Technical Abstract: Introduction: The study objectives were to estimate plasma flunixin (FLU) pharmacokinetic parameters and milk depletion profiles for FLU and its metabolite (5-hydroxy flunixin; 5-OH) after subcutaneous (SC) and intravenous (IV) administration of single and multiple flunixin meglumine (FM) doses to non-lactating (nulliparous and pregnant does) and lactating dairy goats. Analytical methods (ELISA and UPLC- MS/MS) for quantifying plasma FLU concentrations were compared. The final objective was to use regulatory (FDA and EMA) methods to estimate milk withdrawal intervals following extra-label drug use in goats. Methods: FM was administered IV and SC to commercial dairy goats at 1.1 mg/kg for single and multiple doses. Blood and milk samples were analyzed for FLU and 5-OH via UPLC-MS/MS. Plasma samples were also analyzed for FLU concentrations via ELISA. Using statistical approaches recommended by regulatory agencies, milk withdrawal intervals were estimated following FM extra-label use. Results: Following IV administration of a single FM dose, clearances were 127, 199, and 365 mL/kg/hr for non-lactating (NL) pregnant does, NL nulliparous does, and lactating dairy does, respectively. Following multiple SC doses, clearance/F was 199 mL/kg/hr for lactating does. After IV administration of a single MG dose, terminal elimination half-lives were 4.08, 2.87, and 3.77 hr for NL pregnant does, NL nulliparous does, and lactating dairy does, respectively. After multiple SC doses, the terminal elimination half-life was 3.03 hr for lactating dairy does. No significant differences were noted for samples analyzed by UPLC-MS/MS or ELISA. Milk withdrawal intervals ranged from 36-60 hr depending on the regulatory statistical method and dose numbers. Conclusions: Subcutaneous administration of FM to goats results in similar plasma pharmacokinetic parameters as IV administration. ELISA analysis is an alternative method to UPLC-MS/MS for quantifying FLU concentrations in caprine plasma samples. Following FM extra-label administration to dairy goats, clinicians could consider 36-60 hr milk withdrawal intervals.