Yousef Malaz, Mosa Farag E S, Barakat Khaled H, Davies Neal M, Löbenberg Raimar
Faculty of Pharmacy & Pharmaceutical Sciences, Katz Centre for Pharmacy & Health Research, University of Alberta, Edmonton, AB T6G 2E1, Canada.
Pharmaceutics. 2025 Sep 22;17(9):1228. doi: 10.3390/pharmaceutics17091228.
Despite the recognized importance and distinctive characteristics of the intestinal lymphatic pathway in drug absorption, its pharmacokinetic modeling remains largely unexplored. This study aimed to address this gap by developing a physiologically based pharmacokinetic model (PBPK) to represent the oral lymphatic uptake of halofantrine following a fatty meal. : Using GastroPlus™ 9.8.3 and published literature data, halofantrine absorption, distribution, metabolism, and elimination in both fasting and fed states were modeled. As the used software does not directly simulate intestinal lymphatic transport, lymphatic involvement in the fed state was examined indirectly through parameter adjustments such as first-pass metabolism, pKa-driven solubility changes, and bile-salt-mediated solubilization, with the aid of molecular dynamics simulations under post-prandial pH. : The pharmacokinetic models revealed a reduction in the first-pass effect of halofantrine in the fed state compared to that in the fasting state. While adjustments in metabolism kinetics sufficed for constructing a representative PBPK model in the fasting state, capturing the fed-state profile required both modifications to metabolism kinetics and other parameters related to the structural rearrangements of halofantrine driven by the changes in intestinal pH following food intake. These changes were confirmed using molecular dynamics simulations of halofantrine in pHs reflecting the post-prandial conditions. : This study underscores the need for further exploration and direct modeling of intestinal lymphatic uptake via PBPK models, highlighting its underexplored status in simulation algorithms. Moreover, the importance of integrating representative physicochemical factors for drugs, particularly in post-prandial conditions or lipid formulations, is evident. Overall, these findings contribute to advancing predictive regulatory and developmental considerations in drug development using post hoc analyses.
尽管肠道淋巴途径在药物吸收方面具有公认的重要性和独特特征，但其药代动力学建模在很大程度上仍未得到充分探索。本研究旨在通过建立一个基于生理学的药代动力学模型（PBPK）来填补这一空白，以描述脂肪餐后卤泛群的口服淋巴吸收情况。：使用GastroPlus™ 9.8.3和已发表的文献数据，对禁食和进食状态下卤泛群的吸收、分布、代谢和消除进行了建模。由于所使用的软件不能直接模拟肠道淋巴转运，因此借助餐后pH值下的分子动力学模拟，通过诸如首过代谢、pKa驱动的溶解度变化和胆盐介导的增溶等参数调整，间接研究了进食状态下淋巴的参与情况。：药代动力学模型显示，与禁食状态相比，卤泛群在进食状态下的首过效应降低。虽然代谢动力学的调整足以构建禁食状态下具有代表性的PBPK模型，但要捕捉进食状态下的特征，既需要对代谢动力学进行修改，也需要对与食物摄入后肠道pH值变化驱动的卤泛群结构重排相关的其他参数进行修改。这些变化通过在反映餐后条件的pH值下对卤泛群进行分子动力学模拟得到了证实。：本研究强调了通过PBPK模型进一步探索和直接模拟肠道淋巴吸收的必要性，突出了其在模拟算法中未得到充分探索的现状。此外，整合药物代表性物理化学因素的重要性也很明显，特别是在餐后条件或脂质制剂中。总体而言，这些发现有助于通过事后分析推进药物开发中预测性监管和开发方面的考虑。
