INRA, UMR1331 Toxalim, F-31076 Toulouse, France.
BMC Vet Res. 2013 Dec 11;9:250. doi: 10.1186/1746-6148-9-250.
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).
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.
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.
西美考昔是一种新型的犬用 COX-2 抗炎药物。为了确定犬用西美考昔的临床前剂量方案，我们使用了高岭土诱导的爪部炎症可逆模型。使用药代动力学/药效学（PK/PD）建模方法（间接反应模型）建立了剂量方案。
通过建立的炎症模型，我们研究了镇痛、抗炎和退热终点，确定了 12 只比格犬口服（单次剂量）2mg/kg 西美考昔的疗效。对于口服和静脉两种给药途径，我们确定了两组狗，即代谢不良者（PM）和广泛代谢者（EM）。PM 组口服后半衰期为 8.0±0.6 小时，EM 组为 4.6±2.6 小时，静脉给药后分别为 5.6±1.7 小时和 2.7±0.9 小时（均值±标准差）。对于四个终点（体温、爬行速度、地面垂直反应力和临床跛行评分），我们估计了主要药效学参数（效价、疗效和敏感性）。间接效应达到最大值一半时的血浆浓度分别为爬行速度 239μg/L，跛行评分 284μg/L，地面垂直反应力 161μg/L，体温 193μg/L。为了记录西美考昔在目标犬群中分布的可能多态性，我们将西美考昔通过静脉途径给予 40 只狗（四个不同大小的品种）。这些 40 只狗的西美考昔半衰期与 EM 比格犬的半衰期大致相同。因此，我们选择从 EM 比格犬获得的药代动力学和药效学参数来模拟口服给药后的西美考昔剂量-效应关系，从而选择一个剂量方案进行临床试验确认。
西美考昔是一种有效的抗炎、解热和镇痛药物，确定了每日 2mg/kg 的剂量方案用于确认性临床试验。
