Physiologically based in vitro – in vivo correlation of modified release oral formulations with non-linear intestinal absorption: A case study using mirabegron

IF 4.4 2区 医学 Q1 PHARMACOLOGY & PHARMACY European Journal of Pharmaceutics and Biopharmaceutics Pub Date : 2024-09-02 DOI:10.1016/j.ejpb.2024.114479
Yoshinori Takahashi, Atsushi Kambayashi
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Abstract

Establishing an in vitroin vivo correlation (IVIVC) for oral modified release (MR) formulations would make it possible to substitute an in vitro dissolution test for human bioequivalence (BE) studies when changing the formulation or manufacturing methods. However, the number of IVIVC applications and approvals are reportedly low. One of the main reasons for failure to obtain IVIVCs using conventional methodologies may be the lack of consideration of the dissolution and absorption mechanisms of drugs in the physiological environment. In particular, it is difficult to obtain IVIVC using conventional methodologies for drugs with non-linear absorption processes. Therefore, the aim of the present study was to develop a physiologically based biopharmaceutics model (PBBM) that enables Level A IVIVCs for mirabegron MR formulations with non-linear absorption characteristics.

Using human pharmacokinetic (PK) data for immediate-release formulations of mirabegron, the luminal drug concentration-dependent membrane permeation coefficient was calculated through curve fitting. The membrane permeation coefficient data were then applied to the human PK data of the MR formulations to estimate the in vivo dissolution rate by curve fitting. It was assumed that in vivo dissolution could be described using a zero-order rate equation. Furthermore, a Levy plot was generated using the estimated in vivo dissolution rate and the in vitro dissolution rate obtained from the literature. Finally, the dissolution rate of the MR formulations from the Levy plot was applied to the PBBM to predict the oral PK of the mirabegron MR formulations.

This PB-IVIVC approach successfully generated linear Levy plots with slopes of almost 1.0 for MR formulations with different dose strengths and dissolution rates. The Cmax values of the MR formulations were accurately predicted using this approach, whereas the prediction errors for AUC exceeded the Level A IVIVC criteria. This can be attributed to the incomplete description of colonic absorption in the current PBBM.

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基于生理学的体外-体内修正释放口服制剂与非线性肠道吸收的相关性:使用米拉贝琼的案例研究。
为口服修正释放(MR)制剂建立体外-体内相关性(IVIVC),可以在改变制剂或生产方法时,用体外溶出试验替代人体生物等效性(BE)研究。然而,据报道 IVIVC 的申请和批准数量很少。使用传统方法无法获得 IVIVC 的主要原因之一可能是没有考虑到药物在生理环境中的溶解和吸收机制。特别是,对于具有非线性吸收过程的药物,使用传统方法很难获得 IVIVC。因此,本研究旨在开发一种基于生理学的生物药剂学模型(PBBM),该模型可为具有非线性吸收特性的米拉贝琼 MR 制剂提供 A 级 IVIVC。利用米拉贝琼速释制剂的人体药代动力学(PK)数据,通过曲线拟合计算出依赖于管腔药物浓度的膜渗透系数。然后将膜渗透系数数据应用于 MR 制剂的人体药代动力学数据,通过曲线拟合估算体内溶出率。假定体内溶解可以用零阶速率方程来描述。此外,还利用估计的体内溶出率和从文献中获得的体外溶出率生成了列维图。最后,将 Levy 图中的 MR 制剂溶出率应用于 PBBM,以预测米拉贝琼 MR 制剂的口服 PK。这种 PB-IVIVC 方法成功地为不同剂量强度和溶出率的 MR 制剂生成了斜率接近 1.0 的线性列维图。使用这种方法可以准确预测 MR 制剂的 Cmax 值,而 AUC 的预测误差则超过了 A 级 IVIVC 标准。这可归因于目前的 PBBM 对结肠吸收的描述不完整。
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来源期刊
CiteScore
8.80
自引率
4.10%
发文量
211
审稿时长
36 days
期刊介绍: The European Journal of Pharmaceutics and Biopharmaceutics provides a medium for the publication of novel, innovative and hypothesis-driven research from the areas of Pharmaceutics and Biopharmaceutics. Topics covered include for example: Design and development of drug delivery systems for pharmaceuticals and biopharmaceuticals (small molecules, proteins, nucleic acids) Aspects of manufacturing process design Biomedical aspects of drug product design Strategies and formulations for controlled drug transport across biological barriers Physicochemical aspects of drug product development Novel excipients for drug product design Drug delivery and controlled release systems for systemic and local applications Nanomaterials for therapeutic and diagnostic purposes Advanced therapy medicinal products Medical devices supporting a distinct pharmacological effect.
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