The objectives of the study were to evaluate the pharmacokinetics and tolerance of grapiprant, a substrate of the human P-gp transporter, in collies homozygous for MDR1-1Δ when administered at the labeled dosage of 2 mg/kg once daily for 28 days. Twelve collie dogs with homozygous for MDR1-1Δ genotype from a commercial colony were used in the study, eight in the treated group and four as placebo-treated controls. The only treatment-related clinical sign was self-limiting vomiting (in 2/8 treated animals) and the only treatment-related clinical pathological changes seen were a slight decrease in serum albumin in one dog (2.6 g/dL; reference 2.7 to 3.9 g/dL) and total protein (5.1 g/dL; reference 5.5 to 7.7 g/dL). Absorption of grapiprant was rapid with a median T_max of 1 h, C_max of 5.2 μg/mL, AUC_0-24 of 17.3 ± 7.1 h^*μg/mL and median terminal t½ of 4.3 h after the first dose. To determine whether MDR1-1Δ animals handle grapiprant differently from normal dogs, a population pharmacokinetic analysis was performed utilizing data from the collies and historical beagle data. Volume of the peripheral compartment of collies was estimated to be 45% that of beagles, and clearance from the central compartment was 71% less in collies than in beagles. Self-liming vomiting events occurred at a numerically higher rate (2/8; 25%) in this group of P-gp-deficient dogs than seen in a clinical study (17%) composed of various dog breeds but limited numbers in this PK study make comparisons difficult. Grapiprant was otherwise well tolerated in collies homozygous for MDR1-1Δ despite increased drug exposure compared to dogs without this mutation.

中文翻译：

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Galliprant™ 对 MDR1-1Δ 纯合子牧羊犬口服给药的耐受性和药代动力学

该研究的目的是评估 Grapiprant（人 P-gp 转运蛋白的底物）在 MDR1-1Δ 纯合子牧羊犬中的药代动力学和耐受性，当以 2 mg/kg 的标记剂量每天一次给药 28 天时。研究中使用了 12 只来自商业菌落的 MDR1-1Δ 基因型纯合的牧羊犬，8 只用于治疗组，4 只作为安慰剂治疗对照组。唯一与治疗相关的临床症状是自限性呕吐（在 2/8 接受治疗的动物中），唯一与治疗相关的临床病理变化是一只狗的血清白蛋白略有下降（2.6 g/dL；参考 2.7 至 3.9 g/dL）和总蛋白（5.1 g/dL；参考 5.5 至 7.7 g/dL）。grapiprant 的吸收迅速，中位 T _max为 1 h，C _max为 5.2 μg/mL，AUC _0-24为 17.3 ± 7.1 h ^*μg/mL 和第一次给药后 4.3 小时的中位终端 t½。为了确定 MDR1-1Δ 动物处理 grapirant 是否与正常狗不同，利用来自牧羊犬的数据和历史比格犬数据进行了群体药代动力学分析。牧羊犬外围隔室的体积估计为比格犬的 45%，而牧羊犬从中央隔室的清除率比比格犬少 71%。在这组 P-gp 缺乏的狗中，自石灰呕吐事件的发生率（2/8；25%）高于由各种犬种组成的临床研究（17%），但该 PK 中的数量有限研究使比较变得困难。尽管与没有这种突变的狗相比药物暴露增加，但 Grapiprant 在 MDR1-1Δ 纯合牧羊犬中的耐受性良好。