Determination of Safe and Effective Dosing Regimens for Nonsteroidal Anti-inflammatory Drugs in African and Asian Elephants.

Abstract

Arthritis and foot disease are well documented conditions affecting captive elephants that are frequently treated with nonsteroidal anti-inflammatory drugs (NSAIDs). An important consideration regarding efficacy and safety of NSAIDs is the cyclooxygenase isoenzyme (COX-1 or 2) targets and pharmacokinetics of the specific drug. The purpose of this study was to determine the COX preference for each drug in Asian elephants, and to determine a dosing regimen for firocoxib based on pharmacokinetics at two doses (0.01 and 0.1 mg/kg) in Asian and African elephants. Single oral dosing of a commercially available tablet or paste determined a preferred dose. This dose underwent further evaluation via a single i.v. dose, and multiple consecutive doses of both formulations. Studies were performed by participating elephant facilities throughout North America. Samples were subjected to firocoxib analysis using HPLC. Pharmacokinetic data was subjected to non-compartmental analysis. Firocoxib was determined to prefer COX-2 whereas flunixin meglumin preferred COX-1 in vitro in Asian elephants (Elephas magnus). Serum levels of firocoxib were too low at doses of 0.01 mg/kg for pharmacokinetic analysis. Key pharmacokinetic parameters after single dosing of 0.1 mg/kg in African elephants were Cmax (31.3 +/- 6.6 ng/ml for tablets; 44 +/- 12.5 ng/ml for paste), AUC (1588+/-362 H*mg/ml for tablets; 814 H*mg/ml for paste) and elimination half-life (66 hours for tablets; 37 hours for paste). Key parameters for single dosing of 0.1 mg/kg orally in Asian elephan were Cmax (49 +/-3.27 ng/ml for tablets; 62 +/- 14.8 ng/ml for paste), AUC (1332+/-878 H*mg/ml for tablets; 1455+/-634 H*mg/ml for paste) and elimination half-life (34.3 +/-30.3 hours for tablets; 19.9 +/-12.8 hours for paste). After multiple administration, the time to steady-state was 5 days and after 8 days of dosing, the Cmax, (75.8+/-15.5 ng/ml for tablets; 95.5+/-29.3 ng/ml for paste) AUC (6341+/-3003 H*mg/ml for tablets; 5613+/-2262 H*mg/ml for paste) and half-life (84.4+/-32.2 hours for tablets; 62.9+/-2.25 hours for paste) were. All animals tolerated all doses with no apparent adverse events. Based on these data, firocoxib should be an effective, safe and convenient analgesic at 0.1 mg/kg every 24 hours when administered to Asian or African elephants.