摘要
药物临床研究的计算机模拟(CTS)是将计算机模拟技术和药物的临床研究相结合,通过对生物系统的病理生理学和治疗药理学建立数学模型,以仿真的方法模拟试验设计、人体行为、疾病进程和药物行为,来模拟虚拟研究对象的反应。作为药物研发的一部分,药物临床研究的计算机模拟(CTS)有效地解决了新药研发周期长、研制成本高等诸多制约新药研发的现实问题。
在CTS的多种模型中,作为基本的输入/输出模型,药代动力学和药效动力学模型对分析药物和人体的相互作用具有重要意义。本文基于CTS技术,通过仿真分析二房室药代动力学模型和Sigmoid型Emax药效动力学模型中参数对中央室血药浓度和药效的影响,并以模糊集合和模糊逻辑理论为工具,考察模型参数的不确定性对血药浓度的影响。具体工作主要从以下几个方面展开：1、通过仿真考察右美沙芬口服给药二房室药代动力学模型中,中央室血药浓度随吸收速率常数和消除速率常数的变化规律；2、通过仿真分析右美沙芬Sigmoid型Emax药效动力学模型中药效随剂量和各参数的变化规律；3、考虑模型参数的不确定性,应用模糊集合理论以模糊数表示参数,预测血药浓度,通过计算模糊贴近度,分析口服给药二房室模型中各参数对中央室血药浓度的影响；4、以期望血药浓度为参考,设计两变量模糊调节器,通过调整参数来调整血药浓度,考察两变量模糊调节器在调整模型参数时对血药浓度的影响。
通过仿真可以清楚的观察血药浓度和药效与各参数的关系,仿真结果表明不同个体具有不同的药代动力学和药效动力学特征,与临床试验结果具有较好的一致性,对于不同个体的临床给药方案具有重要参考作用,模糊理论作为分析参数不确定性的有力工具,为预测和调节血药浓度提供了科学操作依据。
Clinical trial simulation combines the simulation and clinical trials to generate a response for a virtual subject. It can simulate the trial design, human behavior, disease progess and drug behavior by modeling physiopathology and therapy pharmacology of the biosystem. As one part of the modern drug development, CTS effectively solved many practical problems that restrict drug development such as the long term and high cost.
Among various models of CTS, as the basic input/output model, pharmacokinetics and pharmacodynamics models are of great importance to analyze the interaction between drug and body.
Based on CTS, the influence of parameters on the plasma drug concentration of central compartment and drug effect was analyzed in the two-comparment pharmacokinetic model and Sigmoid Emax pharmacodynamic model by simulating in this thesis. The influence of uncertainty of parameters on the plasma drug concentration was investigated using fuzzy sets and fuzzy logic theory. The main parts of the thesis are as follow:1. The realationship among absorption rate constant, elimination rate constant and the plasma drug concentration characteristics of central compartment in the Dextromethorphan two-comparment pharmacokinetic model with oral administration was investigated by simulating.2. The relationship among dose, parameters and the drug effect in the Dextromethorphan Sigmoid.Emax pharmacodynamic model was investigated by simulating.3. Considering the uncertainty of model parameters, the parameters were presented as fuzzy number and the plasma drug concentration was predicted based on the fuzzy sets theory. The influence of parameters on central compartment plasma drug concentration in the two-compartment model with oral administration was analyzed by calculating fuzzy neartude.4. The two-variable fuzzy adjuster was designed using expected plasma drug concentration as reference to adjust the central compartment plasma drug concentration by altering parameters. The influence of the two-variable fuzzy adjuster on the plasma drug concentration while adjusting model parameters was investigated.
The relationship between drug effect and dose and parameters can be clearly observed via simulation.The results which were accordance with clinical trial demonstrated that every individual is of different PK and PD characteristics. It is of great importance to individualized dosage regimen. Fuzzy theory as a powerful tool analyzing the uncertainty of parameters can offer scientific grounds to predict and adjust plasma drug concentration.
引文
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