Pharmacokinetic/pharmacodynamic modeling for the determination of a cimicoxib dosing regimen in the dog

BMC Veterinary Research

Pierre-Louis Toutain³  Herve P Lefebvre¹  Mathieu Faucher¹  Frederique Woehrle⁴  Marc Schneider⁴  Elisabeth C Jeunesse² 

[1] Unité de Recherche Clinique et Département des Sciences Cliniques, Université de Toulouse, INP, Ecole Nationale Vétérinaire de Toulouse, Toulouse, France;Université de Toulouse, INP, Ecole Nationale Veterinaire de Toulouse, Toxalim, F-31076 Toulouse, France;INRA, UMR1331 Toxalim, F-31076 Toulouse, France;Vétoquinol Research and Development, Lure, France; Vétoquinol S.A., rue des Jeûneurs, Paris, France

关键词: Dosage regimen;    Dog;    NSAID;    Cimicoxib;    Pharmacodynamic;    Pharmacokinetic;   

Others  :  1119388
DOI  :  10.1186/1746-6148-9-250

 received in 2013-07-24, accepted in 2013-12-02,  发布年份 2013

【 摘 要 】

Background

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. Dosage regimens were established using pharmacokinetic/pharmacodynamic (PK/PD) modeling approach (indirect response model).

Results

Analgesic, 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.

Conclusions

Cimicoxib was an efficacious anti-inflammatory, antipyretic and analgesic drug and a dosage regimen of 2 mg/kg daily was determined for confirmatory clinical trials.

【 授权许可】

   
2013 Jeunesse et al.; licensee BioMed Central Ltd.

【 图 表 】

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