药物动力学/药效动力学在研究药物相互作用中的应用─反应曲面模型法研究瑞芬太尼与七氟醚联合应用

中国临床药理学与治疗学 ›› 2007, Vol. 12 ›› Issue (10): 1151-1156.

药物动力学/药效动力学在研究药物相互作用中的应用─反应曲面模型法研究瑞芬太尼与七氟醚联合应用

出版日期:2007-10-26 发布日期:2020-11-04

Pharmacokinetic/pharmacodynamic studies in anestheticdrug-drug interactions-a response surface model with remifentanil and sevoflurane for Chinese adult patients

YANG Lu¹, YANG Ba-xian², ZHANG Li-ping¹, BI Shan-shan³, LU Wei^3,4

¹Department of Anesthesiology, Third Hospital, Peking University, Beijing 100083, China;
²Department of Anesthesiology, People's Hospital, Peking University, Beijing 100083, China;
³Deptartment of Pharmaceutics, School of Pharmaceutical Science, Peking University, Beijing 100083, China;
⁴State Key Lab.of Natural and Biomimetic Drugs, Beijing 100083, China

Online:2007-10-26 Published:2020-11-04
Contact: LU Wei, male, PhD, professor.Tel:86-10-82801717 　E-mail:luwei pk @bjmu.edu.cn
Supported by:
This work was supported by research grants from the National Natural S cience Foundation of China, C30528026, C30672497, and by the China Medi cal Board of New York grants 99-697 and 01-755.

摘要/Abstract

摘要： 目的: 全麻中两种以上的药物合并应用比单一麻醉剂更为有效。本研究是为确定中国成年患者全麻期间合并应用七氟醚与瑞芬太尼时药物相互作用的方式, 并以反应曲面模型法对其进行表述。方法: 1. 试验设计:研究采用平行实验设计, 65 例病人(ASA I 级, 各项指标正常, 无长期服用阿片类药物史) 入选本次试验, 随机选定并维持一定的呼末七氟醚浓度[ ≤2MAC(0. 3 %-3. 4 %) ], 逐渐增加靶控输注的瑞芬太尼浓度(≤10 ng/mL), 观察不同浓度组合时患者对喉镜置入刺激的反应以确定麻醉是否完全。2. 反应曲面模型法进行药物动力学药效动力学分析:两药合用的效果通过对喉镜置入时的反应进行评估, 0 和1 分别代表有或没有体动反应。以下面的药效学模型表述体动反应消失的概率(P)其中Us, Ur 分别为标准化的七氟醚与瑞芬太尼水平;U50 为达最大效应一半时的药物综合标准化水平;r 为形状因子;I (Q) 为药物相互作用的强度函数。模型通过作图、目标函数改变以及参数的生理/临床学的合理性等几方面进行评价。$P=\frac{(Us+Ur)^{r}}{[U_{50}/I(Q)]^{r}+(Us+Ur)^{r}}$ 结果与结论: 研究表明瑞芬太尼与七氟醚合用时为协同式相互作用, 上述反应曲面模型与实际观测值有较好的拟合。应用NONMEM 得到喉镜置入刺激时的参数(RSE %) 为U₅₀=6. 62 (10. 6), C_50,sevo =1. 71 %(12. 9), C_50,remi=12.4 ng/mL(19. 0), I_max =2. 31, Q_max=0. 706 。所得数值的加权残差均小于3 。结果表明与传统方法相比, 反应曲面模型法可以得到较好的拟合质量, 为药物相互作用的研究提供了一种新颖思路和有效手段。

Abstract: AIM: To determine the interactions with response -surface modeling methodologies when sevoflurane (Sevo) and remifentanil (Remi) were administered simultaneously. METHODS: (1) Patients, Study design and drug delivery :Based on parallel slices design, sixtyfive patients were randomly assigned to inhale a specific end-tidal concentration of sevoflurane (0.3 % to 3.4 %), with different level of remifentanil (0 -10 ng mL).The responses to laryngoscopy were observed for each given concentration pair.(2) Pharmacokinetic/pharmacodynamic analysis with response surface mode :The probability of no response (P) was assessed in the modeling process as below. $P=\frac{(Us+Ur)^{r}}{[U_{50}/I(Q)]^{r}+(Us+Ur)^{r}}$ RESULTS AND DISCUSSION:NONMEM estimated average values (RSE %) of the model parameters for laryngoscopy of C_50,Sevo, _C50,remi, U₅₀, r, I_max and Q_max are 1.71 % (12.9), 12.4 ng/mL (19.0), 6.62 (10.6), 1.53 (8.76), 2.31 (8.23), 0.706 (2.46), respectively.The inter-individual variability (CV %) in parameter I_max and inter-occasion variability (S.D.) in this model are 12.7 and 0.0316, respectively.It is concluded that the response-surface modeling approach provided a novel method to study drug-drug interactions.

Key words: drug-drug interactions, synergy, response-surface

. 药物动力学/药效动力学在研究药物相互作用中的应用─反应曲面模型法研究瑞芬太尼与七氟醚联合应用[J]. 中国临床药理学与治疗学, 2007, 12(10): 1151-1156.

YANG Lu, YANG Ba-xian, ZHANG Li-ping, BI Shan-shan, LU Wei. Pharmacokinetic/pharmacodynamic studies in anestheticdrug-drug interactions-a response surface model with remifentanil and sevoflurane for Chinese adult patients[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2007, 12(10): 1151-1156.