Upadacitinib, classified as a highly soluble drug, is commercially marketed as RINVOQ®, a modified-release formulation incorporating hydroxypropyl methylcellulose as a matrix system to target extended release throughout the gastrointestinal (GI) tract. Our study aimed to explore how drug release will occur throughout the GI tract using a plethora of and tools. We built a Physiologically-Based Pharmacokinetic (PBPK) model in GastroPlus™ to predict the systemic concentrations of the drug when administered using dissolution profiles as input to drive luminal dissolution. A series of dissolution experiments were gathered using the USP Apparatus I, III and IV in presence of biorelevant media, simulating both fasted and fed state conditions. A key outcome from the current study was to establish an correlation (IVIVC) between (i) the dissolution profiles obtained from the USP I, III and IV methods and (ii) the fraction absorbed of drug as deconvoluted from the plasma concentration-time profile of the drug. When linking the fraction dissolved as measured in the USP IV model, a Level A IVIVC was established. Moreover, when using the different dissolution profiles as input for PBPK modeling, it was also observed that predictions for plasma C and AUC were most accurate for USP IV compared to the other models (based on predicted observed ratios). Furthermore, the PBPK model has the utility to extract the predicted concentrations at the level of the colon which can be of utmost interest when working with specific assays.

中文翻译：

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体外/计算机工具能否改善口服缓释制剂的结肠浓度估计？乌帕替尼的案例研究


Upadacitinib 被归类为一种高度可溶性药物，在商业上以 RINVOQ® 名义上市，这是一种改良释放制剂，采用羟丙基甲基纤维素作为基质系统，以在整个胃肠道 (GI) 中延长释放为目标。我们的研究旨在探索如何使用大量工具在整个胃肠道中释放药物。我们在 GastroPlus™ 中构建了基于生理学的药代动力学 (PBPK) 模型，以使用溶出曲线作为驱动管腔溶出的输入来预测给药时药物的全身浓度。在生物相关介质存在下，使用 USP 装置 I、III 和 IV 进行了一系列溶出实验，模拟禁食和进食状态条件。当前研究的一个关键成果是建立 (i) 从 USP I、III 和 IV 方法获得的溶出曲线与 (ii) 从血浆浓度-时间曲线解卷积得到的药物吸收分数之间的相关性 (IVIVC)的药物。当将 USP IV 模型中测量的溶解分数联系起来时，建立了 A 级 IVIVC。此外，当使用不同的溶出曲线作为 PBPK 建模的输入时，还观察到与其他模型相比（基于预测的观察到的比率），USP IV 的血浆 Cmax 和 AUC 的预测最准确。此外，PBPK 模型可用于提取结肠水平的预测浓度，这在进行特定测定时可能会引起极大兴趣。