Non Clinical Safety, Janssen R&D, Beerse, Belgium.
Non Clinical Statistics, Janssen R&D, Beerse, Belgium.
Drug Deliv. 2020 Dec;27(1):1597-1607. doi: 10.1080/10717544.2020.1837291.
The blood-brain barrier (BBB) is often a limiting factor for getting drugs in the brain. Bypassing the BBB by intranasal (IN), or also called nose to brain (NTB), route is an interesting and frequently investigated concept for brain drug delivery. However, despite the body of evidence for IN drug delivery in literature over the last decades, reproducibility and interpretation of animal data remain challenging. The objective of this project was to assess the feasibility and value of a standardized IN screening model in rats for the evaluation of direct brain delivery. A chemically diverse set of commercial and internal small molecules were tested in the model with different doses and/or formulations. Data were analyzed using different ways of ratio calculations: blood concentration at time of sacrifice, total exposure in blood (area under the curve, AUC) and the brain or olfactory bulb concentrations. The IN route was compared to another parenteral route to decide if there is potential direct brain transport. The results show that blood and tissue concentrations and ratios are highly variable and not always reproducible. Potential direct brain delivery was concluded for some compounds, however, sometimes depending on the analysis: using blood levels at sacrifice or AUC could lead to different conclusions. We conclude that a screening model for the evaluation of direct brain transport of small molecules is very difficult to achieve and a conclusion based on a limited number of animals with this variability is questionable.
血脑屏障（BBB）通常是将药物输送到大脑的限制因素。通过鼻内（IN）途径，也称为鼻脑（NTB）途径绕过 BBB，是一种用于脑内药物输送的有趣且经常被研究的方法。然而，尽管在过去几十年的文献中有大量关于 IN 药物输送的证据，但动物数据的重现性和解释仍然具有挑战性。本项目的目的是评估标准化 IN 筛选模型在大鼠中用于评估直接脑内给药的可行性和价值。使用不同剂量和/或制剂的一组化学多样化的商业和内部小分子在该模型中进行了测试。使用不同的比率计算方法分析数据：处死时的血液浓度、血液中的总暴露量（曲线下面积，AUC）和大脑或嗅球浓度。将 IN 途径与另一种肠胃外途径进行比较，以确定是否存在潜在的直接脑内转运。结果表明，IN 途径的血液和组织浓度和比率高度可变且并不总是可重现的。对于一些化合物，认为存在潜在的直接脑内转运，但有时取决于分析：使用处死时的血液水平或 AUC 可能会得出不同的结论。我们得出结论，用于评估小分子直接脑内转运的筛选模型非常难以实现，并且基于具有这种变异性的有限数量的动物得出的结论是值得怀疑的。
