Pharmacokinetics, pharmacodynamics, toxicology and therapeutics of mavacoxib in the dog: a review

Abstract

Mavacoxib is a novel nonsteroidal anti-inflammatory drug (NSAID), with a preferential action on the cyclooxygenase (COX)-2 isoform of COX and a long duration of action. It is classified chemically as a member of the sulphonamide subgroup of coxibs. Mavacoxib is highly lipid but very poorly water soluble. In the dog, the pharmacokinetic (PK) profile comprises very slow body clearance, long elimination half-life and a relatively large distribution volume. Biotransformation and renal excretion are very limited, and elimination occurs primarily by biliary secretion and excretion of unchanged drug in faeces. The PK profile of mavacoxib differs quantitatively between young healthy dogs (Beagles and mongrels) and clinical cases with osteoarthritis (OA). In OA dogs, mavacoxib exhibits a much longer terminal half-life, associated principally with their greater median body weight compared with dogs used in preclinical studies. There is also some evidence of breed differences and a small effect of age on mavacoxib PK in the OA canine population. The pharmacodynamics (PD) of mavacoxib has been established: (i) in whole blood assays at the molecular level (inhibition of COX-1 and COX-2 isoforms); (ii) in preclinical models of inflammation and pain; and (iii) in clinical OA subjects treated with mavacoxib. The dosage schedule of mavacoxib for clinical use has been determined by owner and veterinary clinical assessments and is supported by integration of PK and PD preclinical data with clinical responses in canine disease models and in dogs with naturally occurring OA. The dosage regimen has been further confirmed by correlating levels of inhibition of COX isoforms in in vitro whole blood assays with plasma concentrations of mavacoxib achieved in OA dogs. In addition to the specific properties of mavacoxib, some general aspects of the PK and PD of other agents of the NSAID group, together with pathophysiological and clinical aspects of OA, are reviewed, as a basis for correlating with the safety and efficacy of mavacoxib in therapeutic use. Integration of PK and PD data suggests that the recommended dosage regimen of 2 mg/kg bw once for 14 days, followed by administration at monthly intervals, is optimal from both efficacy and safety perspectives and is further confirmed by clinical field studies.

Comparative population pharmacokinetics and absolute oral bioavailability of COX-2 selective inhibitors celecoxib, mavacoxib and meloxicam in cockatiels (Nymphicus hollandicus)

“…For mavacoxib and meloxicam, EHR has been described in literature 19 , 21 , 26 , 33 , 34 . The present study was not able to demonstrate a pronounced presence of EHR in cockatiels, possibly due to the limited blood collection points at the secondary peaks.…”

“…Consequently, in dogs a low clearance and prolonged elimination half-life (t 1/2el ) are reported. Therefore a less frequent dosing is necessary, which contributes to an improved therapeutic compliance 19 – 21 . Initially, a classical dose determination study indicated that a dose of 4 mg/kg BW is necessary to exhibit clinical efficacy.…”

The selective cyclooxygenase‐2 inhibitor mavacoxib (Trocoxil) exerts anti‐tumour effects in vitro independent of cyclooxygenase‐2 expression levels

“…Positive results from pre‐clinical and clinical trials, in which coxibs have been used as a preventative agent or as a therapeutic in combination with either chemotherapeutics or surgery, demonstrates the potential of using such drugs as cancer therapeutics . In veterinary medicine, mavacoxib (Trocoxil) is of interest because it is currently licensed to treat pain and inflammation associated with canine osteoarthritis where long‐term (up to 6 months) treatment is required . Mavacoxib is unique in the family of NSAIDs and coxibs as it exhibits a low clearance rate, a relatively large distribution volume and a long plasma half‐life, resulting in a reduced dosing regimen.…”

“…17,[30][31][32][33] In veterinary medicine, mavacoxib (Trocoxil) is of interest because it is currently licensed to treat pain and inflammation associated with canine osteoarthritis where long-term (up to 6 months) treatment is required. 34 Mavacoxib is unique in the family of NSAIDs and coxibs as it exhibits a low clearance rate, a relatively large distribution volume and a long plasma half-life, resulting in a reduced dosing regimen. Consequently, the potential clinical benefit of using mavacoxib is high.…”

Evaluation of Terminalia chebula Extract for Anti-Arthritic Efficacy and Safety in Osteoarthritic Dogs

“…Additionally, NSAIDs have been reported to inhibit bone healing [55]. Recently, Lees et al [56] indicated that mavacoxib (Trocoxil, a selective COX-2 inhibitor) can be an alternative to NSAIDs that indiscriminately inhibit both COX-1 and COX-2. Of course, the use of mavacoxib also has limitations with regard to dog weight (contraindicated in dogs weighing <5 kg) and duration of treatment (not for >6.5 months).…”