Mukherjee A, Hale V G, Borga O, Stein R
Division of Anti-inflammatory, Analgesic and Ophthalmologic Drug Products, Food and Drug Administration, Rockville, MD 20857, USA.
Inflamm Res. 1996 Nov;45(11):531-40. doi: 10.1007/BF02342223.
Relevance of the preclinical pharmacodynamic, toxicity and pharmacokinetic parameters predicting the clinical potency of nonsteroidal antiinflammatory drugs (NSAIDs) was evaluated.
Data for oral potencies of 24 NSAIDs in rats were collected from the literature and from New Drug Applications with respect to the following parameters: antiinflammatory, analgesic, antipyretic, acute ulcerogenic activities, acute toxicity, in vitro inhibition of prostaglandin synthesis, acid dissociation constant (pKa), octanol-water partition coefficient and elimination half-life.
Data for most of the in vivo parameters in rats were collected following single dose administration with the exception of adjuvant arthritis. Single and daily clinical doses were considered. All of these NSAIDs have been approved for marketing although not all have been sold in the USA.
The preclinical data were compared to human dose (unit or daily doses) using single and multiple stepwise regression analyses.
Analyses suggest that NSAIDs are effective in all models of preclinical tests for fever, pain and inflammation, however, carrageenin-induced rat paw edema model is clearly the best predictor of human dose. Rank order of preclinical models for predicting human dose is carrageenin > yeast induced fever > pressure induced pain = adjuvant arthritis in rats. The analysis suggested that the pain and adjuvant arthritis models in rats may also involve a prostaglandin independent mechanism. Of the two physicochemical factors tested, pKa contributed best to the carrageenin model towards predicting the clinical potency of NSAIDs. Mathematical relationships between human dose, carrageenin ED50 and pKa were established that may assist in the future clinical development of NSAIDs.
Carrageenin-induced paw edema model in rats is the most robust predictor of the clinical potency of NSAIDs. Acid dissociation constant (pKa) appears to be a secondary contributor to the potency of NSAIDs. The relevance of the data analyses for developing cyclooxygenase-2 (COX-2) selective NSAIDs is discussed.
评估预测非甾体抗炎药（NSAIDs）临床效力的临床前药效学、毒性和药代动力学参数的相关性。
从文献和新药申请中收集了24种NSAIDs在大鼠体内口服效力的数据，涉及以下参数：抗炎、镇痛、解热、急性致溃疡活性、急性毒性、体外前列腺素合成抑制、酸解离常数（pKa）、辛醇 - 水分配系数和消除半衰期。
除佐剂性关节炎外，大多数大鼠体内参数的数据是在单次给药后收集的。考虑了单次和每日临床剂量。所有这些NSAIDs均已获批上市，尽管并非所有药物都在美国销售。
使用单步和多步逐步回归分析将临床前数据与人体剂量（单位剂量或每日剂量）进行比较。
分析表明，NSAIDs在所有临床前发热、疼痛和炎症模型中均有效，然而，角叉菜胶诱导的大鼠足爪水肿模型显然是人体剂量的最佳预测指标。预测人体剂量的临床前模型的排序为：角叉菜胶＞酵母诱导的发热＞压力诱导的疼痛 = 大鼠佐剂性关节炎。分析表明，大鼠的疼痛和佐剂性关节炎模型可能还涉及一种不依赖前列腺素的机制。在所测试的两个物理化学因素中，pKa对角叉菜胶模型预测NSAIDs临床效力的贡献最大。建立了人体剂量、角叉菜胶ED50和pKa之间的数学关系，这可能有助于NSAIDs未来的临床开发。
角叉菜胶诱导的大鼠足爪水肿模型是NSAIDs临床效力最可靠的预测指标。酸解离常数（pKa）似乎是NSAIDs效力的次要影响因素。讨论了数据分析对开发环氧化酶 - 2（COX - 2）选择性NSAIDs的相关性。
