Koopmans R, Dingemanse J, Danhof M, Horsten G P, van Boxtel C J
Department of Medicine, University of Amsterdam, The Netherlands.
Clin Pharmacol Ther. 1988 Jul;44(1):14-22. doi: 10.1038/clpt.1988.106.
The effect of midazolam on alpha-activity of the EEG and latency of the P-100 of the visual evoked response (VER) was studied in six healthy subjects. Drug concentration was related to effect with the Emax model that was used with either a threshold drug concentration or a sigmoid exponent. An effect compartment was included in the pharmacokinetic-pharmacodynamic model. Four subjects showed hysteresis, and mean values of half-lives-k(eo) ranged from 0.26 to 0.60 hour. Mean values of EC50 ranged from 42.0 to 48.1 ng/ml. Goodness of fit did not differ significantly between the sigmoid Emax model and the threshold Emax model. The sigmoid exponent estimated was 3.7 +/- 1.8 (EEG, mean +/- SD) and 2.9 +/- 1.4 (VER); the threshold concentration was estimated at 15.7 +/- 11.1 ng/ml (EEG) and 11.3 +/- 7.0 ng/ml (VER). We conclude that the Emax model adequately describes the relationship between midazolam concentration and effect and that the sigmoid exponent can be substituted by a threshold drug concentration, with a comparable fit of the model to the data.
在六名健康受试者中研究了咪达唑仑对脑电图α活动及视觉诱发电位（VER）P-100潜伏期的影响。药物浓度与效应的关系采用Emax模型，该模型使用阈值药物浓度或S形指数。药代动力学-药效学模型中纳入了效应室。四名受试者出现滞后现象，消除半衰期（k(eo)）的平均值在0.26至0.60小时之间。半数有效浓度（EC50）的平均值在42.0至48.1 ng/ml之间。S形Emax模型和阈值Emax模型的拟合优度无显著差异。估计的S形指数为3.7±1.8（脑电图，平均值±标准差）和2.9±1.4（VER）；阈值浓度估计为15.7±11.1 ng/ml（脑电图）和11.3±7.0 ng/ml（VER）。我们得出结论，Emax模型充分描述了咪达唑仑浓度与效应之间的关系，并且S形指数可以用阈值药物浓度替代，模型对数据的拟合相当。
