Modh Harshvardhan, Fang Daniel Juncheng, Ou Yi Hsuan, Yau Jia Ning Nicolette, Kovshova Tatyana, Nagpal Shakti, Knoll Julian, Wallenwein Chantal M, Maiti Kuntal, Bhowmick Subhas, Gelperina Svetlana, Pastorin Giorgia, Wacker Matthias G
National University of Singapore, Faculty of Science, Department of Pharmacy, Singapore.
Lomonosov Moscow State University, Leninskiye Gory 1, 119991 Moscow, Russia; D. Mendeleev University of Chemical Technology of Russia, Miusskaya pl. 9, 125047 Moscow, Russia.
Int J Pharm. 2021 Oct 25;608:121073. doi: 10.1016/j.ijpharm.2021.121073. Epub 2021 Sep 2.
A growing number of nanomedicines entered the clinical trials and improved our understanding of the in vivo responses expected in humans. The in vitro drug release represents an important critical quality attribute involved in pharmacokinetics. Establishing in vitro-in vivo relationships for nanomedicines requires a careful analysis of the clinical data with respect to the unique differences between drugs and nanomedicines. Also, the biorelevant assay must reflect the release mechanism of the carrier. Four drug delivery systems of doxorubicin were evaluated for their in vitro release behavior under biorelevant conditions using the dispersion releaser. The pharmacokinetics observed during the first-in-men clinical trials were analyzed using a custom-made physiologically-based nanocarrier biopharmaceutics model. The drug product Lipodox® and the clinical candidate NanoCore-7.4 were evaluated to validate the model. Afterward, the in vivo performances of the preclinical candidates NanoCore-6.4 and doxorubicin-loaded nano-cellular vesicle technology systems (an extracellular vesicle preparation) were predicted. In vitro and in vivo release were in good correlation as indicated by the coefficients of determination of 0.98648 (NanoCore-7.4) and 0.94107 (Lipodox®). The predictions required an estimation of the carrier half-life in blood circulation leading to considerable uncertainty. Still, the simulations narrow down the possible scenarios in the clinical evaluation of nanomedicines and provide a valuable addition to animal studies.
越来越多的纳米药物进入临床试验，增进了我们对人体预期体内反应的了解。体外药物释放是涉及药代动力学的一个重要关键质量属性。建立纳米药物的体外-体内关系需要仔细分析临床数据，以考量药物与纳米药物之间的独特差异。此外，生物相关性测定必须反映载体的释放机制。使用分散释放器评估了四种阿霉素药物递送系统在生物相关条件下的体外释放行为。利用定制的基于生理学的纳米载体生物药剂学模型分析了首次人体临床试验期间观察到的药代动力学。对药品Lipodox®和临床候选药物NanoCore-7.4进行了评估，以验证该模型。之后，预测了临床前候选药物NanoCore-6.4和载阿霉素纳米细胞囊泡技术系统（一种细胞外囊泡制剂）的体内性能。体外和体内释放具有良好的相关性，NanoCore-7.4的决定系数为0.98648，Lipodox®的决定系数为0.94107。预测需要估计载体在血液循环中的半衰期，这导致了相当大的不确定性。尽管如此，这些模拟缩小了纳米药物临床评估中可能出现的情况范围，并为动物研究提供了有价值的补充。
