Ohri Shivam, Parekh Paarth, Nichols Lauren, Rajan Shiny Amala Priya, Cirit Murat
Javelin Biotech, Inc., 299 Washington Street, Woburn, Massachusetts 01801, USA.
bioRxiv. 2024 Jul 22:2024.07.17.603946. doi: 10.1101/2024.07.17.603946.
Polypharmacy-related drug-drug interactions (DDIs) are a significant and growing healthcare concern. Increasing number of therapeutic drugs on the market underscores the necessity to accurately assess the new drug combinations during pre-clinical evaluation for DDIs. primary human hepatocyte (PHH)-only models are commonly used only for perpetrator DDI studies due to their rapid loss of metabolic function. But co-culturing non-human cells with human PHHs can stabilize metabolic activity and be utilized for both perpetrator and victim studies, though this raises concerns about human specificity for accurate clinical assessment. In this study, we evaluated Liver Tissue Chip (LTC) with PHH-only liver microphysiological system (MPS) for DDI induction studies. Liver MPS from three individual donors maintained their functional and metabolic activity for up to 4 weeks demonstrating suitability for long-term pharmacokinetics (PK) studies. The responses to rifampicin induction of three PHH donors were assessed using CYP activity and mRNA changes. Additionally, victim PK studies were conducted with midazolam (high clearance) and alprazolam (low clearance) following rifampicin-mediated induction which resulted in a 2-fold and a 2.6-fold increase in midazolam and alprazolam intrinsic clearance values respectively compared to the untreated liver MPS. We also investigated the induction effects of different dosing regimens of the perpetrator drug (rifampicin) on CYP activity levels, showing minimal variation in the intrinsic clearance of the victim drug (midazolam). This study demonstrates the utility of the LTC for liver-specific DDI induction studies, providing a translational experimental system to predict clinical clearance values of both perpetrator and victim drugs.
多重用药相关的药物相互作用（DDIs）是一个重大且日益受到关注的医疗问题。市场上治疗药物数量的增加凸显了在临床前评估药物相互作用时准确评估新药组合的必要性。仅使用原代人肝细胞（PHH）的模型通常仅用于肇事药物相互作用研究，因为其代谢功能会迅速丧失。但是将非人类细胞与人PHH共培养可以稳定代谢活性，并可用于肇事药物和受害药物研究，不过这引发了对准确临床评估的人类特异性的担忧。在本研究中，我们评估了仅含PHH的肝微生理系统（MPS）的肝组织芯片（LTC）用于药物相互作用诱导研究。来自三个个体供体的肝MPS在长达4周的时间内保持其功能和代谢活性，表明适用于长期药代动力学（PK）研究。使用CYP活性和mRNA变化评估了三个PHH供体对利福平诱导的反应。此外，在利福平介导的诱导后，对咪达唑仑（高清除率）和阿普唑仑（低清除率）进行了受害药物PK研究，结果显示与未处理的肝MPS相比，咪达唑仑和阿普唑仑的内在清除率值分别增加了2倍和2.6倍。我们还研究了肇事药物（利福平）不同给药方案对CYP活性水平的诱导作用，结果显示受害药物（咪达唑仑）的内在清除率变化最小。本研究证明了LTC在肝脏特异性药物相互作用诱导研究中的实用性，提供了一个转化实验系统来预测肇事药物和受害药物的临床清除率值。
