Lemmens H J, Dyck J B, Shafer S L, Stanski D R
Department of Anesthesia, Stanford University School of Medicine, CA.
Clin Pharmacol Ther. 1994 Sep;56(3):261-71. doi: 10.1038/clpt.1994.136.
We determined the possible benefits of a new opioid, trefentanil, relative to fentanyl and alfentanil using high-resolution pharmacokinetic-pharmacodynamic modeling and computer simulations of clinical dosing scenarios.
First, we determined in nine volunteers the electroencephalographic (EEG) effects and the trefentanil infusion rate that gave maximal EEG changes in 3 to 10 minutes. Then, in a crossover fashion in five volunteers, we compared the pharmacokinetics and EEG pharmacodynamics of trefentanil with fentanyl and alfentanil. Finally, we used computer simulations to predict offset of opioid effects of trefentanil, fentanyl, and alfentanil when given in different dosing schemes.
The pharmacokinetic-pharmacodynamic profile of trefentanil was similar to alfentanil, except for a higher elimination clearance. Trefentanil versus alfentanil pharmacokinetic parameters were as follows: Elimination clearance, 0.444 +/- 0.073 versus 0.184 +/- 0.031 L/min; steady-state distribution volume, 37 +/- 7 versus 23 +/- 3 L; and elimination half-life, 127 +/- 24 versus 114 +/- 19 minutes. Trefentanil versus alfentanil pharmacodynamics were as follows: the equilibration half-time between EEG effect and arterial drug concentration, 1.2 +/- 0.5 versus 0.6 +/- 0.4 minutes; and the concentration resulting in 50% of maximal EEG effect, 429 +/- 313 versus 577 +/- 273 ng/ml. The pharmacokinetic-pharmacodynamic profile of fentanyl was significantly different from trefentanil and alfentanil. Simulation of effect compartment concentration decay curves after variable-length infusions predicted more rapid recovery from trefentanil than from alfentanil or fentanyl.
We suggest that high-resolution pharmacokinetic-pharmacodynamic studies and computer simulations of clinical dosing scenarios may have significant usefulness in appreciating differences between new and established drugs in early phase I studies.
我们使用高分辨率药代动力学 - 药效学模型以及临床给药方案的计算机模拟，确定了新型阿片类药物曲芬太尼相对于芬太尼和阿芬太尼可能具有的益处。
首先，我们在9名志愿者中确定了脑电图（EEG）效应以及在3至10分钟内产生最大EEG变化的曲芬太尼输注速率。然后，在5名志愿者中采用交叉方式，我们比较了曲芬太尼与芬太尼和阿芬太尼的药代动力学和EEG药效学。最后，我们使用计算机模拟来预测曲芬太尼、芬太尼和阿芬太尼在不同给药方案下阿片类药物效应的消退情况。
曲芬太尼的药代动力学 - 药效学特征与阿芬太尼相似，只是消除清除率更高。曲芬太尼与阿芬太尼的药代动力学参数如下：消除清除率，0.444±0.073对0.184±0.031 L/分钟；稳态分布容积，37±7对23±3 L；消除半衰期，127±24对114±19分钟。曲芬太尼与阿芬太尼的药效学参数如下：EEG效应与动脉血药浓度之间的平衡半衰期，1.2±0.5对0.6±0.4分钟；产生最大EEG效应50%时的浓度，429±313对577±273 ng/ml。芬太尼的药代动力学 - 药效学特征与曲芬太尼和阿芬太尼显著不同。对不同时长输注后效应室浓度衰减曲线的模拟预测，曲芬太尼的恢复比阿芬太尼或芬太尼更快。
我们认为，高分辨率药代动力学 - 药效学研究以及临床给药方案的计算机模拟在认识I期早期研究中新药与已上市药物之间的差异方面可能具有重要作用。
