Translational DMPK, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark; CNS Drug Delivery and Barrier Modelling, University of Copenhagen, Universitetsparken 2, 2100 København Ø, Denmark.
Translational DMPK, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark; PKPD Modelling & Simulation, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
Eur J Pharm Sci. 2023 Nov 1;190:106554. doi: 10.1016/j.ejps.2023.106554. Epub 2023 Aug 3.
The application of Göttingen minipigs for non-rodent pharmacokinetics (PK) and drug safety testing has seen a dramatic increase in recent years. The aim of this study was to determine the total and unbound brain-to-plasma ratios (K and K) for a diverse set of reference compounds in female Göttingen minipigs and compare these with K values from other species to assess the suitability of Göttingen minipigs as a model for CNS drug safety testing and brain PK in clinical translation. The reference set consisted of 17 compounds with varying physico-chemical properties and included known human P-glycoprotein (P-gp) substrates. The results of the study showed, that minipig K and K values for the tested compounds were in the range 0.03-86 and 0.02-2.4 (n = 3-4) respectively. The K values were comparable between minipig and rat for a large proportion of the compounds (71% within 2-fold, n = 17). Comparisons of brain penetration across several species for a subset of reference compounds revealed that minipig values were quite similar to those of rat, dog, monkey and human. The study highlighted that the largest K species differences were observed for compounds classified as transporter substrates (e.g. cimetidine, risperidone, Way-100635 and altanserin). In conclusion these brain penetration data add substantially to the available literature on PK and drug disposition for minipigs and support use of Göttingen minipig as a non-rodent drug safety model for CNS drug candidates and as a brain PK model for clinical translation.
近年来，哥廷根小型猪在非啮齿类药代动力学（PK）和药物安全性测试中的应用有了显著的增加。本研究的目的是确定一系列不同参考化合物在雌性哥廷根小型猪体内的总脑-血浆比（K 和 K），并将这些结果与其他物种的 K 值进行比较，以评估哥廷根小型猪作为 CNS 药物安全性测试和临床转化中脑 PK 模型的适用性。参考集由 17 种具有不同理化性质的化合物组成，包括已知的人 P-糖蛋白（P-gp）底物。研究结果表明，所测试化合物的小型猪 K 和 K 值分别在 0.03-86 和 0.02-2.4 之间（n = 3-4）。对于大部分化合物（n = 17，在 2 倍以内占 71%），小型猪和大鼠的 K 值之间具有可比性。对一组参考化合物在几种物种中的脑穿透性进行比较，结果表明小型猪的值与大鼠、狗、猴子和人类的值相当相似。该研究表明，对于被归类为转运体底物的化合物（例如西咪替丁、利培酮、WAY-100635 和阿坦色林），观察到的 K 值物种间差异最大。总之，这些脑穿透数据大大增加了关于小型猪 PK 和药物处置的可用文献，并支持将哥廷根小型猪用作 CNS 药物候选物的非啮齿类药物安全性模型，以及用于临床转化的脑 PK 模型。
