中国人口老龄化的程度日益加深，预计到 2050 年，中国老年人口数量将达到总人口的 3l%，进入重度老龄化阶段。老年人随着年龄的增长，复杂的病理生理学、器官功能改变会影响药物在体内的吸收、分布、代谢、排泄（Absorption,distribution, metabolism and excretion, ADME）过程，进而导致老年人群的药效和安全性差异大。同时，由于多重用药、药物不良反应发生率显著升高，老年人群中普遍存在较高的用药风险。但与老年人群用药复杂形成鲜明对比的是，我国老年人群给药剂量普遍存在无据可依的局面。因此，明确老年常用药物体内药动学特征及相互作用规律，制定合理用药方案，实现个体化精准治疗，是解决老年人群个体化用药难题的根本途径。基于生理的药代动力学（Physiologically Based Pharmacokinetic，PBPK）模型可以将药物的理化性质和人体系统生物学参数整合到动态模型中，来预测药物在体内的药代动力学（Pharmacokinetics, PK）特征。本论文拟利用 PBPK 模型在中国老年人群临床用药中进行探索和实践，评估多种老年人常用药物在人体的药物暴露情况，探索影响药物暴露的重要生理因素，为我国老年人群的合理用药用提供科学支持。本论文共分为三部分：第一部分，建立 50 种老年人常用药物的 PBPK 模型： 选取 50 个老年人的常用药物，收集药物的理化性质参数、ADME 信息、临床药动学数据，建立药物在中国老年人群中的 PBPK 模型，预测老年人群在临床常用给药方案下的药代动力学特征，为临床剂量优化、治疗药物监测（Therapeutic drug monitoring, TDM）、个体化给药提供参考和借鉴。第二部分，探索 PBPK 模型在治疗药物监测中的应用：治疗药物监测作为一种重要的患者管理方法，广泛应用于多种药物的临床诊疗。本部分以第一部分中 4 个代表性药物为目标：抗抑郁药舍曲林，吗氯贝胺，镇静催眠药阿普唑仑，抗帕金森药金刚烷胺，利用所建立的 PBPK 模型预测药物在老年人群中达到治疗参考范围的合理剂量，为老年人群个体化用药提供参考。第三部分，进行 PBPK 模型在特殊制剂的拓展研究：建立了伐尼克兰鼻喷雾制剂半机制化的 PBPK 模型，探索在中国和美国不同年龄段人群中鼻腔给药伐尼克兰后全身和鼻腔部位的药代动力学特征，以支持伐尼克兰鼻喷雾制剂在中国的临床开发和上市，并预测中国老年人群中的药物暴露。

China's population is aging increasingly, and it is expected that by 2050, the elderly population in China will reach 3l% of the total population, entering a stage of severe aging. As the elderly age, complex pathophysiological and organ functional changes can affect the absorption, distribution, metabolism, and excretion (ADME) processes of drugs in the body, leading to increased differences in drug efficacy and safety among the elderly population. At the same time, due to the significant increase in the incidence of multiple medication and adverse drug reactions, there is generally a higher risk of medication use among the elderly population. However, in stark contrast to the complexity of medication among the elderly population, there is a general lack of evidence for the dosage of medication given to the elderly population in China. Therefore, clarifying the in vivo pharmacokinetics and potential drug-drug interactions in the elderly, developing reasonable medication plans, and achieving personalized and precise treatment are the fundamental ways to solve the problem of individualized medication in the elderly population. Physiologically based pharmacokinetic (PBPK) model can integrate physicochemical properties of drugs and human physiological parameters into the dynamic model, which can predict the pharmacokinetics (PK) characteristics of drugs in vivo. This paper intends to establish PBPK models in Chinese elderly population to evaluate exposure of commonly used drugs in the elderly and explore important physiological affecting factors, so as to provide scientific support for rational use of drugs in the elderly population.

  The full text of this paper is divided into three parts:

(1) The first part established PBPK models of 50 drugs commonly used in the elderly: Fifty common drugs for the elderly were selected, physicochemical property parameters, pharmacokinetic parameters and clinical pharmacokinetic data were collected. And then, PBPK models of 50 drugs in Chinese elderly population were established and applied to simulate the PK characteristics of the elderly under common clinical administration schemes, providing guidance for clinical dose optimization, therapeutic drug monitoring (TDM) and individualized drug administration.

(2) The second part explored the application of PBPK model in therapeutic drug monitoring: As an important method in patient management, TDM is widely used in clinical monitoring of multiple drugs. In this part, four representative drugs in the first part were taken as targets: sertraline，moclobemide (anti-depressant drug), ilaprazole (sedative-hypnotic drug), and amantadine (anti-parkinson drug). The PBPK models were used to predict the reasonable dosages, so that the drug concentrations in vivo could be within the therapeutic reference range. Finally, such predictions could provide reference for individualized drug use in the elderly population.

(3) The third part is the expansion of PBPK model in special preparation: a semi-mechanistic PBPK model of varenicline nasal spray was established to explore the systemic and nasal PK characteristics in Chinese and American populations with different ages after intranasal administration, so as to support the clinical development and marketing of varenicline nasal spray in China. And then, the model was used to predict drug exposure in the Chinese elderly population.