在体外/in silico工具可以改善口服延长释放配方的结肠度估计吗? 一个用upadacitinib的案例研究
Alessia Favaron1, Bart Hens2, Maiara Camotti Montanha2
1UCL School of Pharmacy, University College London, London WC1N 1AX, UK.
概括
这项研究开发了一种基于生理学的药理动力学 (PBPK) 模型,以预测Upadacitinib在胃肠道 (GI) 中的释放. 通过USP IV溶解方法,成功地确定了体外与体内相关性 (IVIVC).
科学领域:
- 药理动力学和药物输送方法
- 在维特罗和在模拟模型.
背景情况:
- 乌帕达西替尼 (RINVOQ®) 是一种使用基甲基纤维素进行延长胃肠道 (GI) 药物释放的修饰释放配方.
- 了解整个胃肠道的药物释放特征对于修改释放配方至关重要.
研究的目的:
- 通过体外和in silico方法研究Upadacitinib在整个胃肠道释放的情况.
- 为了确定Upadacitinib溶解的体外-体内相关性 (IVIVC).
- 评估不同USP设备的预测准确性,用于PBPK建模.
主要方法:
- 在GastroPlusTM中开发一种生理学基础的药理动力学 (PBPK) 模型.
- 使用USP Apparatus I,III和IV与生物相关介质 (禁食和养状态) 的体外溶解实验.
- 血度-时间概况的解卷,以确定吸收的分数.
主要成果:
- 在将USP IV溶解数据与吸收的药物分数联系起来时,确定了A级IVIVC.
- 对Cmax和AUC的PBPK模型预测最准确的是使用USP IV溶解档案.
- PBPK模型可以预测结肠水平的药物度.
结论:
- 该USP IV装置适用于建立Upadacitinib修饰释放配方的A级IVIVC.
- 使用USP IV溶解数据的PBPK建模提供了系统性药物暴露的准确预测.
- 该PBPK模型提供了有关肠道药物释放和吸收的宝贵见解.
相关概念视频
01:16Methods for Studying Drug Absorption: In vitro
233
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...
233
01:09Methods for Studying Drug Absorption: In situ
231
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,...
231
01:20Factors Affecting Dissolution: Drug Permeability, Stability and Stereochemistry
202
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...
202
01:27Factors Influencing Drug Absorption: Drug Dissolution
480
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...
480
01:24One-Compartment Open Model: Wagner-Nelson and Loo Riegelman Method for ka Estimation
487
This lesson introduces two critical methods in pharmacokinetics, the Wagner-Nelson and Loo-Riegelman methods, used for estimating the absorption rate constant (ka) for drugs administered via non-intravenous routes. The Wagner-Nelson method relates ka to the plasma concentration derived from the slope of a semilog percent unabsorbed time plot. However, it is limited to drugs with one-compartment kinetics and can be impacted by factors like gastrointestinal motility or enzymatic degradation.
On...
On...
487
01:22Factors Influencing Drug Absorption: Physicochemical Parameters
269
The physicochemical characteristics of drugs play a crucial role in formulating stable and bioavailable drug products. The solubility of a drug, governed by the varying pH along the GI tract and its dissociation constant (pKa), is pivotal in determining its ionization state and absorption rate. Notably, weak acids and bases remain unionized and are absorbed more rapidly.
Enhanced drug absorption can be achieved by reducing particle sizes and increasing surface areas, thereby facilitating...
Enhanced drug absorption can be achieved by reducing particle sizes and increasing surface areas, thereby facilitating...
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