Sanofi R&D, Montpellier, France; Institute for Regenerative Medicine and Biotherapy, Université et CHU de Montpellier, INSERM, Montpellier, France.
Sanofi R&D, Montpellier, France.
J Pharm Sci. 2018 Jul;107(7):1957-1972. doi: 10.1016/j.xphs.2018.03.001. Epub 2018 Mar 7.
The objective was to compare, with the same data set, the predictive performance of 3 in vitro assays of hepatic clearance (CL), namely, micropatterned cocultures (also referring to HepatoPac) and suspension as well as monolayer hepatocytes to define which assay is the most accurate. Furthermore, existing in vitro-to-in vivo extrapolation (IVIVE) methods were challenged to verify which method is the most predictive (i.e., direct scaling method without binding correction, conventional method based either on the unbound fraction in plasma (fu) according to the free-drug hypothesis, or based on an fu value adjusted for the albumin [ALB]-facilitated hepatic uptake phenomenon). Accordingly, the role of ALB binding was specifically challenged, and consequently, the ALB production was monitored in parallel to the metabolic stability. The ALB concentration data were used to compare the in vitro assays and to adjust the value of fu of each drug to mimic the ALB-facilitated hepatic uptake phenomenon. The results confirmed that the direct and conventional IVIVE methods generally overpredicted and underpredicted the CL in vivo in humans, respectively. However, the underprediction of the conventional IVIVE method based on fu was significantly reduced from data generated with the HepatoPac system compared with the 2 other in vitro assays, which is possibly because that system is producing ALB at a rate much closer to the in vivo condition in liver. Hence, these observations suggest that the presence of more ALB molecules per hepatocyte in that HepatoPac system may have facilitated the hepatic uptake of several bound drugs because their intrinsic CL was increased instead of being decreased by the ALB binding effect. Accordingly, the IVIVE method based on the fu value adjusted for the ALB-facilitated uptake phenomenon gave the lowest prediction bias from the statistical analyses. This study indicated that the HepatoPac system combined with the adjusted value of fu was the most reliable IVIVE method and revealed the importance of quantifying the in vitro-to-in vivo variation of ALB concentration to improve the CL predictions, which would help any future physiologically based pharmacokinetics modeling exercise.
目的是使用相同的数据集比较 3 种体外肝清除率 (CL) 测定方法的预测性能，即微图案共培养物（也称为 HepatoPac）和悬浮以及单层肝细胞，以确定哪种测定方法最准确。此外，还对现有的体外向体内外推（IVIVE）方法进行了挑战，以验证哪种方法最具预测性（即无结合校正的直接缩放法，基于根据游离药物假说的血浆中游离分数 (fu) 的传统方法，或基于白蛋白 [ALB] 促进肝摄取现象调整的 fu 值）。因此，特别挑战了 ALB 结合的作用，并且因此，平行监测代谢稳定性的同时监测 ALB 的产生。使用 ALB 浓度数据来比较体外测定方法，并调整每种药物的 fu 值以模拟 ALB 促进的肝摄取现象。结果证实，直接和传统的 IVIVE 方法通常分别过高和过低预测了人体中的体内 CL。然而，与其他 2 种体外测定方法相比，基于 fu 的传统 IVIVE 方法的低估从 HepatoPac 系统产生的数据中显著减少，这可能是因为该系统以更接近体内肝脏的速度产生 ALB。因此，这些观察结果表明，在 HepatoPac 系统中，每个肝细胞中存在更多的 ALB 分子可能促进了几种结合药物的肝摄取，因为它们的内在 CL 增加而不是被 ALB 结合作用降低。因此，基于调整了 ALB 促进摄取现象的 fu 值的 IVIVE 方法从统计学分析中给出了最低的预测偏差。这项研究表明，HepatoPac 系统与调整后的 fu 值相结合是最可靠的 IVIVE 方法，并揭示了量化体外到体内 ALB 浓度变化以改善 CL 预测的重要性，这将有助于任何未来基于生理学的药代动力学建模工作。
