在监管审查中以生理学为基础的药理动力学建模和仿真:美国FDA CBER经验和观点
Million A Tegenge1, Osman N Yogurtcu2, Artur A Belov2
1Office of Biostatistics and Pharmacovigilance, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA. million.tegenge@fda.hhs.gov.
The AAPS journal
|October 9, 2025
概括
基于生理学的药理动力学 (PBPK) 建模通过整合数据来预测药物行为来帮助药物开发. 这一分析回顾了PBPK的PBPK.
科学领域:
- 药理学和药物开发领域
- 生物技术是生物技术.
- 监管科学 监管科学
背景情况:
- 基于生理学的药理动力学 (PBPK) 建模是基于模型的药物开发 (MIDD) 的关键组成部分.
- PBPK集成了各种数据来预测药物药理动力学 (PK),剂量,作用机制 (MoA) 和药理动力学 (PD).
研究的目的:
- 在美国食品和药物管理局的生物评估和研究中心 (CBER) 分析PBPK提交的景观.
- 总结CBER对生物制剂的PBPK建模和仿真 (M&S) 的经验,包括治疗性蛋白质,细胞和基因疗法.
- 讨论PBPK在新型疗法中的应用,例如基于腺相关病毒 (AAV) 的基因疗法和信使RNA (mRNA) 疗法.
主要方法:
- 对PBPK提交给CBER的申请进行了景观分析.
- 审查CBER与生物制品PBPK M&S的经验.
- 在治疗性蛋白质开发中PBPK应用的案例研究分析.
- 对AAV和mRNA治疗的PBPK潜力的讨论.
主要成果:
- PBPK M&S越来越多地用于支持细胞和基因疗法的临床试验设计,剂量选择和PK/PD预测.
- PBPK 建模有助于对生物产品的安全性和有效性的定量理解.
- PBPK正在成为开发新型治疗模式的有价值工具.
结论:
- 在CBER,PBPK建模是基于模型的药物开发 (MIDD) 的强大工具.
- PBPK M&S支持开发安全有效的治疗蛋白质,细胞疗法和基因疗法.
- 预计PBPK的应用将扩大,特别是在AAV和mRNA产品等先进疗法中.
相关概念视频
01:20Pharmacokinetic Models: Overview
Pharmacokinetic models utilize mathematical analysis to achieve a detailed quantitative understanding of a drug's life cycle within the body. They are instrumental in simulating a drug's pharmacokinetic parameters, predicting drug concentrations over time, optimizing dosage regimens, linking concentrations with pharmacologic activity, and estimating potential toxicity.
There are three primary types of models: empirical, compartment, and physiological. Empirical models, with minimal assumptions,...
There are three primary types of models: empirical, compartment, and physiological. Empirical models, with minimal assumptions,...
01:15Model Approaches for Pharmacokinetic Data: Physiological Models
Physiological models in pharmacokinetics are instrumental in understanding the distribution and elimination of drugs within the body. These models describe the drug concentration within target organs, influenced by factors such as drug uptake, tissue volume, and blood flow. Drug uptake is governed by the partition coefficient, which signifies the drug concentration ratio in tissue to that in the blood. The blood flow rate to a specific tissue is expressed as Qt, and the rate of change in tissue...
01:26Pharmacokinetic Models: Comparison and Selection Criterion
Physiological and compartmental models are valuable tools used in studying biological systems. These models rely on differential equations to maintain mass balance within the system, ensuring an accurate representation of the dynamic processes at play.
Physiological models take a detailed approach by considering specific molecular processes. They can predict drug distribution, metabolism, and elimination changes, providing a comprehensive understanding of how drugs interact with the body.
Physiological models take a detailed approach by considering specific molecular processes. They can predict drug distribution, metabolism, and elimination changes, providing a comprehensive understanding of how drugs interact with the body.
01:14Pharmacokinetic–Pharmacodynamic Relationship: Model Components
Pharmacokinetic-pharmacodynamic (PK–PD) modeling is essential in drug development and clinical pharmacology. It provides a quantitative framework to predict drug behavior and response over time. This approach integrates pharmacokinetics (PK), which describes the drug's absorption, distribution, metabolism, and excretion, with pharmacodynamics (PD), which characterizes the drug’s biological effects and mechanisms of action.The disposition kinetics of a drug determine its plasma...
01:27Pharmacodynamic Models: Overview
Pharmacodynamic (PD) responses describe the interaction between a drug and its biological target, culminating in a physiological effect. These responses can be classified into different types: continuous variables, such as blood glucose levels; categorical outcomes, like survival rates; and time-to-event metrics, such as disease progression. Understanding and modeling PD responses are critical for optimizing drug efficacy and safety.PD models describe the relationship between drug concentration...
01:15Impact of Pharmacokinetic–Pharmacodynamic Models: Regulatory Decisions
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