年龄和性别对瑞芬太尼药代动力学和药效学的影响。I. 模型建立。

Influence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil. I. Model development.

作者信息

Minto C F, Schnider T W, Egan T D, Youngs E, Lemmens H J, Gambus P L, Billard V, Hoke J F, Moore K H, Hermann D J, Muir K T, Mandema J W, Shafer S L

机构信息

Department of Anesthesia, Stanford University School of Medicine, California, USA.

出版信息

Anesthesiology. 1997 Jan;86(1):10-23. doi: 10.1097/00000542-199701000-00004.

DOI:10.1097/00000542-199701000-00004

PMID:9009935

Abstract

BACKGROUND

Previous studies have reported conflicting results concerning the influence of age and gender on the pharmacokinetics and pharmacodynamics of fentanyl, alfentanil, and sufentanil. The aim of this study was to determine the influence of age and gender on the pharmacokinetics and pharmacodynamics of the new short-acting opioid remifentanil.

METHODS

Sixty-five healthy adults (38 men and 27 women) ages 20 to 85 y received remifentanil by constant-rate infusion of 1 to 8 micrograms.kg-1.min-1 for 4 to 20 min. Frequent arterial blood samples were drawn and assayed for remifentanil concentration. The electroencephalogram was used as a measure of drug effect. Population pharmacokinetic and pharmacodynamic modeling was performed using the software package NONMEM. The influence of volunteer covariates were analyzed using a generalized additive model. The performances of the simple (without covariates) and complex (with covariates) models were evaluated prospectively in an additional 15 healthy participants ages 41 to 84 y.

RESULTS

The parameters for the simple three-compartment pharmacokinetic model were V1 = 4.98 l, V2 = 9.01 l, V3 = 6.54 l, Cl1 = 2.46 l/min, Cl2 = 1.69 l/min, and Cl3 = 0.065 l/min. Age and lean body mass were significant covariates. From the ages of 20 to 85 y, V1 and Cl1 decreased by approximately 25% and 33%, respectively. The parameters for the simple sigmoid Emax pharmacodynamic model were Ke0 = 0.516 min-1, E0 = 20 Hz, Emax = 5.62 Hz, EC50 = 11.2 ng/ml, and gamma = 2.51. Age was a significant covariate of EC50 and Ke0, with both decreasing by approximately 50% for the age range studied. The complex pharmacokinetic-pharmacodynamic model performed better than did the simple model when applied prospectively.

CONCLUSIONS

This study identified (1) an effect of age on the pharmacokinetics and pharmacodynamics of remifentanil; (2) an effect of lean body mass on the pharmacokinetic parameters; and (3) no influence of gender on any pharmacokinetic or pharmacodynamic parameter.

摘要

背景

先前的研究报告了年龄和性别对芬太尼、阿芬太尼和舒芬太尼的药代动力学和药效学影响的相互矛盾的结果。本研究的目的是确定年龄和性别对新型短效阿片类药物瑞芬太尼的药代动力学和药效学的影响。

方法

65名年龄在20至85岁之间的健康成年人（38名男性和27名女性）以1至8微克·千克-1·分钟-1的恒定速率输注瑞芬太尼4至20分钟。频繁采集动脉血样并检测瑞芬太尼浓度。脑电图用作药物效应的指标。使用NONMEM软件包进行群体药代动力学和药效学建模。使用广义相加模型分析志愿者协变量的影响。在另外15名年龄在41至84岁之间的健康参与者中对简单（无协变量）和复杂（有协变量）模型的性能进行前瞻性评估。

结果

简单三室药代动力学模型的参数为V1 = 4.98升，V2 = 9.01升，V3 = 6.54升，Cl1 = 2.46升/分钟，Cl2 = 1.69升/分钟，Cl3 = 0.065升/分钟。年龄和瘦体重是显著的协变量。在20至85岁之间，V1和Cl1分别下降了约25%和33%。简单S形Emax药效学模型的参数为Ke0 = 0.516分钟-1，E0 = 20赫兹，Emax = 5.62赫兹，EC50 = 11.2纳克/毫升，γ = 2.51。年龄是EC50和Ke0的显著协变量，在所研究的年龄范围内两者均下降了约50%。前瞻性应用时，复杂的药代动力学-药效学模型比简单模型表现更好。