Abstract
BackgroundCimicoxib is a new coxib anti-inflammatory drug for use in the dog. To determine a preclinical dosage regimen for cimicoxib in dog, a reversible model of kaolin–induced paw inflammation was used. Dosage regimens were established using pharmacokinetic/pharmacodynamic (PK/PD) modeling approach (indirect response model).ResultsAnalgesic, anti-inflammatory and antipyretic endpoints investigated with the inflammation model established the efficacy of cimicoxib at a dose of 2 mg/kg administered orally (single dose) in 12 beagle dogs.For both the oral and IV route of administration two groups of dogs to be identified namely Poor Metabolizers (PM) and Extensive Metabolizers (EM).The terminal half-life after oral administration was 8.0 ± 0.6 h for the PM and 4.6 ± 2.6 h for the EM groups, with the corresponding values after the IV route being 5.6 ± 1.7 h and 2.7 ± 0.9 h (mean ± SD).The main pharmacodynamic parameters (potency, efficacy, and sensitivity) were estimated for four endpoints (body temperature, creeping speed, ground vertical reaction force and clinical lameness score). The plasma concentration corresponding to half the maximum of the indirect effect were 239 μg/L for creeping speed, 284 μg/L for the lameness score, 161 μg/L for the ground reaction vertical force and 193 μg/L for the body temperature.To document possible polymorphism of the cimicoxib disposition in the target dog population, cimicoxib was administered by the intravenous route to 40 dogs (four different sized breeds). The cimicoxib half-lives in these 40 dogs were of same order of the magnitude as those of the EM beagle dogs. Thus pharmacokinetic and pharmacodynamic parameters obtained from the EM beagle dogs were selected to simulate the dose-effect relationship of cimicoxib after an oral administration allowing a dosage regimen to be selected for confirmation by a clinical trial.ConclusionsCimicoxib was an efficacious anti-inflammatory, antipyretic and analgesic drug and a dosage regimen of 2 mg/kg daily was determined for confirmatory clinical trials.
Highlights
Cimicoxib is a new coxib anti-inflammatory drug for use in the dog
It was shown that firocoxib was able to slow down wound healing in a canine gastric mucosal injury model but by a mechanism independent of prostaglandin synthesis [8] meaning that a high COX-1/COX2 selectivity is not the only pharmacodynamic (PD) endpoint to consider when discussing Non-steroidal anti inflammatory drug (NSAID) g.i.t tolerability
For the COXIB class, the plasma clearances are very different among substances from a very low clearance for mavacoxib (2.7 mL/kg/h) [10] to a rather high clearance for robenacoxib (810 mL/kg/h) [11] and firocoxib (462 ml/kg/h) [6] which explains the large differences in half-lives namely 17.3 days for mavacoxib, 0.63 h for robenacoxib and 5.9 h for firocoxib
Summary
Cimicoxib is a new coxib anti-inflammatory drug for use in the dog. To determine a preclinical dosage regimen for cimicoxib in dog, a reversible model of kaolin–induced paw inflammation was used. It was shown that firocoxib was able to slow down wound healing in a canine gastric mucosal injury model but by a mechanism independent of prostaglandin synthesis [8] meaning that a high COX-1/COX2 selectivity is not the only pharmacodynamic (PD) endpoint to consider when discussing NSAID g.i.t tolerability Another factor of COXIB tolerability is the selected dosage regimen; a dosage regimen depends on two pharmacokinetic (PK) parameters (namely plasma clearance and bioavailability for the extravascular route of administration) and of one PD parameter (namely the efficacious plasma concentration that reflects the drug potency). In the present paper this point was addressed for cimicoxib by investigating the PK profiles in breeds other than beagle dogs
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