Biopharmaceutics Group, Global Clinical Management, Dr. Reddy's Laboratories Ltd., Integrated Product Development Organization (IPDO), Hyderabad, Telangana, India.
Biopharm Drug Dispos. 2023 Jun;44(3):195-220. doi: 10.1002/bdd.2339. Epub 2022 Dec 14.
The greater utilization and acceptance of physiologically-based pharmacokinetic (PBPK) modeling to evaluate the potential metabolic drug-drug interactions is evident by the plethora of literature, guidance's, and regulatory dossiers available in the literature. In contrast, it is not widely used to predict transporter-mediated DDI (tDDI). This is attributed to the unavailability of accurate transporter tissue expression levels, the absence of accurate in vitro to in vivo extrapolations (IVIVE), enzyme-transporter interplay, and a lack of specific probe substrates. Additionally, poor understanding of the inhibition/induction mechanisms coupled with the inability to determine unbound concentrations at the interaction site made tDDI assessment challenging. Despite these challenges, continuous improvements in IVIVE approaches enabled accurate tDDI predictions. Furthermore, the necessity of extrapolating tDDI's to special (pediatrics, pregnant, geriatrics) and diseased (renal, hepatic impaired) populations is gaining impetus and is encouraged by regulatory authorities. This review aims to visit the current state-of-the-art and summarizes contemporary knowledge on tDDI predictions. The current understanding and ability of static and dynamic PBPK models to predict tDDI are portrayed in detail. Peer-reviewed transporter abundance data in special and diseased populations from recent publications were compiled, enabling direct input into modeling tools for accurate tDDI predictions. A compilation of regulatory guidance's for tDDI's assessment and success stories from regulatory submissions are presented. Future perspectives and challenges of predicting tDDI in terms of in vitro system considerations, endogenous biomarkers, the use of empirical scaling factors, enzyme-transporter interplay, and acceptance criteria for model validation to meet the regulatory expectations were discussed.
生理药代动力学（PBPK）模型在评估潜在代谢性药物相互作用方面的广泛应用和接受程度，从文献中大量可用的文献、指南和监管档案中可见一斑。相比之下，它并未广泛用于预测转运体介导的药物相互作用（tDDI）。这归因于缺乏准确的转运体组织表达水平、缺乏准确的体外向体内外推（IVIVE）、酶-转运体相互作用以及缺乏特异性探针底物。此外，对抑制/诱导机制的理解不足，加上无法确定相互作用部位的游离浓度，使得 tDDI 评估具有挑战性。尽管存在这些挑战，但 IVIVE 方法的不断改进使得 tDDI 的准确预测成为可能。此外，将 tDDI 外推至特殊（儿科、孕妇、老年）和患病（肾功能不全、肝功能不全）人群的必要性正在获得动力，并得到监管机构的鼓励。本综述旨在探讨当前的最新技术，并总结当代关于 tDDI 预测的知识。详细描述了静态和动态 PBPK 模型预测 tDDI 的当前理解和能力。编译了来自近期出版物的特殊和患病人群中经同行评审的转运体丰度数据，可直接输入建模工具以进行准确的 tDDI 预测。介绍了 tDDI 评估的监管指南和监管提交的成功案例。讨论了从体外系统考虑、内源性生物标志物、经验性缩放因子的使用、酶-转运体相互作用以及满足监管期望的模型验证接受标准等方面预测 tDDI 的未来展望和挑战。
