从活体预测溶解到虚拟生物等价性:一种 GastroPlus®驱动的框架,用于通用Candesartan Cilexetil片
Hao Ruan1,2, Xiaoting Geng2, Zijing Situ3
1College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, China.
Pharmaceuticals (Basel, Switzerland)
|April 26, 2025
概括
这项研究引入了一种新的计算方法来评估仿制药的质量. 该框架成功预测了candesartan cilexetil的生物等价性,提供了更快,更便宜的评估.
科学领域:
- 药理动力学和药物新陈代谢
- 制药技术 制药技术 制药技术
- 计算机建模 计算建模
背景情况:
- 坎德萨坦西莱克塞特是BCSII类前药物,由于溶解性差,P-gp排泄和第一通代谢,它面临生物利用性挑战.
- 评估通用candesartan cilexetil的生物等价性是复杂的.
- 基于生理学的药理动力学 (PBPK) 建模和生物相关溶解正在推进生物等价性评估.
研究的目的:
- 开发和验证GastroPlus®驱动的框架,使用体内预测溶解 (IPD) 和虚拟生物等效 (VBE).
- 为了评估通用candesartan cilexetil片的质量的一致性.
- 证明该框架对生物等价性具有预测能力.
主要方法:
- 在GastroPlus®中开发了一种口服PBPK模型.
- 使用基于酸盐缓冲器的流通细胞溶解装置建立了IPD方法.
- 来自四家通用candesartan cilexetil片制造商的体外溶解数据被用于VBE模拟.
主要成果:
- VBE模拟表明,只有一个仿制品 (A公司) 与参考产品实现了虚拟生物等价性.
- 这些发现与现实世界质量一致性评估相关.
- 该框架表现出强大的预测准确性.
结论:
- 拟议的IPD和VBE框架有效地将体外溶解数据与体内生物等价性结果相结合.
- 这种方法为配方优化提供了具有成本效益和效率的战略.
- 该框架适用于仿制药的临床前生物等价性评估.
相关概念视频
01:15Theories of Dissolution: Diffusion Layer Model
600
Dissolution, the process by which drug particles dissolve in a solvent, is explained by the diffusion layer model, a theoretical framework that simulates the absorption of oral drugs and allows us to analyze experimental data.
This process starts with a thin layer, saturated with the drug, forming at the interface between the solid and liquid. The solute then diffuses from this layer into the main solution. The Noyes-Whitney equation suggests that the rate of dissolution relies on the diffusion...
This process starts with a thin layer, saturated with the drug, forming at the interface between the solid and liquid. The solute then diffuses from this layer into the main solution. The Noyes-Whitney equation suggests that the rate of dissolution relies on the diffusion...
600
01:16Methods for Studying Drug Absorption: In vitro
168
In vitro experiments are crucial for understanding the transport and absorption of drugs through biological materials. These studies employ varied methods such as the diffusion cell method, the everted sac technique, and the everted ring technique.
The diffusion cell method uses a two-compartment cell, including a donor compartment with the drug solution, which simulates the environment where the drug is applied, and a receptor compartment with a buffer solution, which simulates the environment...
The diffusion cell method uses a two-compartment cell, including a donor compartment with the drug solution, which simulates the environment where the drug is applied, and a receptor compartment with a buffer solution, which simulates the environment...
168
01:21Factors Affecting Dissolution: Drug pKa, Lipophilicity and GI pH
788
Drug absorption within the gastrointestinal (GI) tract is a complex process influenced by several critical factors, including the site pH, the drug's dissociation constant (pKa), and the drug's lipophilicity. The GI tract exhibits a pH gradient, with an acidic environment in the stomach and a more alkaline environment in the small intestine. This pH variation directly affects the ionization state of drugs.
A drug's pKa and the pH of the gastrointestinal (GI) tract play crucial roles...
A drug's pKa and the pH of the gastrointestinal (GI) tract play crucial roles...
788
01:27Factors Influencing Drug Absorption: Drug Dissolution
372
The pharmacokinetic journey of drugs from solid oral dosage forms into systemic circulation is multifaceted. It begins with disintegration, a prerequisite ensuring a solid dosage form's subdivision into minute particles. Dissolution occurs next as these granulated entities solubilize in gastrointestinal fluids. This solubilization is crucial for the succeeding stage, permeation, which describes the traversal of the drug across the intestinal membrane and its subsequent entry into the blood...
372
01:20Factors Affecting Dissolution: Drug Permeability, Stability and Stereochemistry
148
Orally administered drugs primarily enter the systemic circulation via passive diffusion through the intestinal membranes. The drug's absorption is influenced by drug stability in the gastrointestinal GI tract, membrane permeability, the surface area available for absorption, luminal drug concentration, and residence time in the lumen. Drug permeability can be enhanced by adjusting the lipophilicity, polarity, or molecular size of the drug, promoting its passive transport across intestinal...
148
01:09Methods for Studying Drug Absorption: In situ
175
In situ experiments, such as the Doluisio method and Single-Pass Perfusion technique, provide critical insights into drug uptake by simulating in vivo conditions for drug absorption.
The Doluisio method involves perfusing a prepared segment of a rat's small intestine with a solution of radiolabeled drug and a non-absorbable marker. This helps to differentiate between absorbed and non-absorbed drug concentrations. The intestinal segment is connected at both ends using tubing and syringes,...
The Doluisio method involves perfusing a prepared segment of a rat's small intestine with a solution of radiolabeled drug and a non-absorbable marker. This helps to differentiate between absorbed and non-absorbed drug concentrations. The intestinal segment is connected at both ends using tubing and syringes,...
175