Abstract：
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 in vitro and in silico tools. We built a Physiologically-Based Pharmacokinetic (PBPK) model in GastroPlus™ to predict the systemic concentrations of the drug when administered using in vitro dissolution profiles as input to drive luminal dissolution. A series of in vitro 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 in vitro-in vivo 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 Cmax and AUC were most accurate for USP IV compared to the other models (based on predicted versus 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 in vitro assays.
摘要：
Upadacitinib,被归类为高度可溶性药物，在商业上作为RINVOQ®销售，一种包含羟丙基甲基纤维素作为基质系统的调释制剂,以在整个胃肠(GI)道中靶向延长释放。我们的研究旨在探索如何使用大量的体外和硅片工具在整个胃肠道中释放药物。我们在GastroPlus™中建立了基于生理学的药代动力学（PBPK）模型，以预测使用体外溶出曲线作为驱动腔溶出的输入给药时药物的全身浓度。使用USP仪器I收集了一系列体外溶出实验，III和IV在生物相关培养基的存在下，模拟禁食和进食状态条件。当前研究的关键结果是建立（i）从USPI获得的溶出曲线之间的体外-体内相关性（IVIVC）。III和IV方法和（ii）从药物的血浆浓度-时间曲线解卷积的药物吸收部分。当连接USPIV模型中测量的溶解部分时，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,USPIV对血浆Cmax和AUC的预测最准确(基于预测与观察比).此外，PBPK模型具有在结肠水平提取预测浓度的效用,当与特定体外测定一起工作时,这可能是最感兴趣的。
