Development of a Universal In Vivo Predictive Dissolution Method for a Borderline BCS III/IV Drug Guided by Modeling and Simulations─Acyclovir as a Case Study.

IF 4.5 2区医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL

Molecular Pharmaceutics Pub Date : 2025-09-22 DOI:10.1021/acs.molpharmaceut.5c00981

Mauricio A García, Fernando Tapia, Benjamín Escares, Peter Langguth

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引用次数: 0

Abstract

Establishing in vivo predictive dissolution (IPD) conditions requires the consideration of biopredictive aspects during dissolution. For acyclovir, lower dose strengths (200 and 400 mg) can dissolve completely in the gastrointestinal fluids. However, luminal concentrations after administering the highest strength (800 mg) exceed the BCS solubility threshold. Given its poor permeability, sink conditions are not granted for the highest strength. In this study, a universal IPD method for acyclovir tablets was developed using the mini-vessel/mini-paddle apparatus. Computational simulations in a physiologically based pharmacokinetic (PBPK) model further guided the development. Apparatuses with different volumes and stirring conditions were explored, and results served as input for the model. Dissolution of 800 mg of acyclovir tablets in 900 mL of medium largely overpredicted observed plasma profiles due to poor resemblance of nonsink conditions in the lumen. Conversely, dissolution in the mini-vessel filled with 135 mL of HCl, pH 2.0, at 150 rpm, produced accurate predictions of plasma profiles, without affecting previous successful predictions with the lowest strength tablets. Furthermore, in-human and virtual bioequivalence studies confirmed the predictive potential of this method. Therefore, the aforementioned dissolution conditions can be considered as a universal IPD method for acyclovir immediate-release tablets.

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以建模和模拟为指导的边缘性BCS III/IV药物体内溶出度预测方法的开发──以阿昔洛韦为例。

建立体内预测溶出（IPD）条件需要考虑溶出过程中的生物预测方面。对于阿昔洛韦，较低剂量（200和400毫克）可以完全溶解在胃肠道液体中。然而，给予最高强度（800毫克）后的管腔浓度超过了BCS溶解度阈值。由于其渗透性差，因此不允许有最高强度的下沉条件。本研究采用微型血管/微型桨片装置，建立了一种通用的阿昔洛韦片剂IPD方法。基于生理的药代动力学（PBPK）模型的计算模拟进一步指导了该研究的发展。探索了不同体积和搅拌条件下的设备，并将结果作为模型的输入。800mg阿昔洛韦片剂在900ml培养基中的溶出度在很大程度上高估了观察到的血浆谱，因为它们与管腔内的非沉降条件不太相似。相反，在装有135 mL HCl， pH为2.0的微型容器中，以150 rpm的速度溶解，可以准确预测血浆谱，而不影响先前使用最低剂量片剂的成功预测。此外，人体和虚拟生物等效性研究证实了该方法的预测潜力。因此，上述溶出度条件可作为阿昔洛韦速释片的通用IPD方法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Pharmaceutics 医学-药学

CiteScore

8.00

自引率

6.10%

发文量

391

审稿时长

2 months

期刊介绍： Molecular Pharmaceutics publishes the results of original research that contributes significantly to the molecular mechanistic understanding of drug delivery and drug delivery systems. The journal encourages contributions describing research at the interface of drug discovery and drug development. Scientific areas within the scope of the journal include physical and pharmaceutical chemistry, biochemistry and biophysics, molecular and cellular biology, and polymer and materials science as they relate to drug and drug delivery system efficacy. Mechanistic Drug Delivery and Drug Targeting research on modulating activity and efficacy of a drug or drug product is within the scope of Molecular Pharmaceutics. Theoretical and experimental peer-reviewed research articles, communications, reviews, and perspectives are welcomed.