Pharmacokinetics and metabolism of orally administered firocoxib, a novel second generation coxib, in horses

Abstract

The primary objective of this study was to determine the pharmacokinetic profile of firocoxib, a novel second generation coxib, in horses. Horses were administered either a single oral or intravenous dose of firocoxib at 0.1 mg/kg in a two-period crossover study with 12 animals. The dosage was based on previously determined pharmacodynamic parameters. Oral firocoxib was well absorbed with an average bioavailability (absolute) of 79% and a Cmax of 75 ng/mL at 3.9 h. The average elimination half-life was 30 h. Following intravenous administration the average Cmax was 210 ng/mL and the elimination half-life was 34 h. The area under the curve [AUC(0-tlast)] was 1.8 microg.h/mL for the oral dose and 2.3 microg.h/mL for the intravenous dose. Firocoxib was widely distributed with a volume of distribution value of 1.7 L/kg for the intravenous dose. Biotransformation of firocoxib was via dealkylation and glucuronidation to inactive metabolites, namely descyclopropylmethylfirocoxib and its glucuronide conjugate. Urinary excretion was the major route of elimination, and the clearance rate was 37 mL/h/kg.

Use of firocoxib for the treatment of equine osteoarthritis

“…As of April 2014, when used at the recommended dose, all three formulations fell below the US Equestrian Federation (USEF) 2014 threshold (240 ng/mL) for the entire sampling period in all horses, and below the Racing Medication and Testing Consortium threshold (20 ng/mL) in all horses 7 days after administration of the final dose. 48,49 A similar study has been performed with six healthy adult horses administered 0.1 mg/kg oral paste firocoxib for 12 consecutive days and 12 healthy adult horses administered 0.2 mg/kg IV firocoxib for 9 consecutive days. 50 In this study, the mean steady-state plasma concentration was 130±36 ng/ mL and 229±73 ng/mL for the oral paste and tablet form, respectively, and the maximum concentration after the last oral dose was 173±44 ng/mL.…”

A Brief Overview of the Coxib Drugs in the Veterinary Field

“…Chemically it is a 3-cyclopropymethoxy-5,5-dimethyl-4-[4-(methyl sulfonyl) phenyl]-2-(5H)-furanone and its molecular weight is 336.402 g moL −1 . The drug was launched several years ago and in this short time, the pharmacokinetic properties of firocoxib in dogs and horses have already been well established (Kvaternick et al, 2007a;2007b;Letendre et al, 2008). Firocoxib is available as a chewable tablet oral preparation which has been approved in the European Union for dogs at a once daily administration of 5 mg kg −1 .…”

“…Firocoxib is available as a chewable tablet oral preparation which has been approved in the European Union for dogs at a once daily administration of 5 mg kg −1 . In addition, firocoxib, as an oral paste was approved by FDA for the control of pain and inflammation associated with osteoarthritis in horses at 0.1 mg kg −1 once daily (Kvaternick et al, 2007b). In dogs, following PO administration (5 mg kg −1 ), firocoxib was well absorbed and eliminated by hepatic metabolism and fecal excretion with an elimination half-life of 8 h (Kvaternick et al, 2007a).…”

“…Due to its lipophilic and non-ionizable nature, firocoxib was widely distributed with a volume of distribution value of 1.7 L kg −1 after intravenous administration in horse. Firocoxib showed a longer halflife compared with other NSAIDs, such as phenylbutazone and flunixin meglumine (Kahn and Line, 2010;Kvaternick et al, 2007b).…”

Nonsteroidal Anti‐Inflammatory Drugs and Corticosteroids

“…It is approved for osteoarthritis in dogs, and is effective in decreasing urate-induced synovitis, pain, inflammation, and lameness (Drag et al, 2007). In horses, the pharmacokinetics after single (Kvaternick et al, 2007) and multiple (Letendre et al, 2008) oral dosing have been described, and firocoxib is comparable in efficacy to phenylbutazone for treatment of osteoarthritis (Doucet et al, 2008). For horses with small intestinal colic, firocoxib may be preferred over flunixin meglumine, as it inhibits recovery of ischemia-injured mucosa to a lesser degree (Cook et al, 2009).…”