Quantitative in vitro to in vivo extrapolation for developmental toxicity potency of valproic acid analogues

体内 基于生理学的药代动力学模型 发育毒性 药理学 毒性 IVIVC公司 效力 体外 丙戊酸 化学 药代动力学 体外毒理学 生物 生物化学 胎儿 有机化学 溶解试验 神经科学 生物技术 癫痫 怀孕 遗传学 生物制药分类系统
作者
Xiaoqing Chang,Jessica Palmer,Un Jung Lee,Patricia Ceger,Kamel Mansouri,Catherine S. Sprankle,Shannon Bell,John F. Wambaugh,David Allen,Nicole Kleinstreuer
出处
期刊:Teratology [Wiley]
卷期号:114 (16): 1037-1055 被引量:4
标识
DOI:10.1002/bdr2.2019
摘要

Abstract Background The developmental toxicity potential (dTP) concentration from the devTOX quick Predict (devTOX qP ) assay, a metabolomics‐based human induced pluripotent stem cell assay, predicts a chemical's developmental toxicity potency. Here, in vitro to in vivo extrapolation (IVIVE) approaches were applied to address whether the devTOX qP assay could quantitatively predict in vivo developmental toxicity lowest effect levels (LELs) for the prototypical teratogen valproic acid (VPA) and a group of structural analogues. Methods VPA and a series of structural analogues were tested with the devTOX qP assay to determine dTP concentration and we estimated the equivalent administered doses (EADs) that would lead to plasma concentrations equivalent to the in vitro dTP concentrations. The EADs were compared to the LELs in rat developmental toxicity studies, human clinical doses, and EADs reported using other in vitro assays. To evaluate the impact of different pharmacokinetic (PK) models on IVIVE outcomes, we compared EADs predicted using various open‐source and commercially available PK and physiologically based PK (PBPK) models. To evaluate the effect of in vitro kinetics, an equilibrium distribution model was applied to translate dTP concentrations to free medium concentrations before subsequent IVIVE analyses. Results The EAD estimates for the VPA analogues based on different PK/PBPK models were quantitatively similar to in vivo data from both rats and humans, where available, and the derived rank order of the chemicals was consistent with observed in vivo developmental toxicity. Different models were identified that provided accurate predictions for rat prenatal LELs and conservative estimates of human safe exposure. The impact of in vitro kinetics on EAD estimates is chemical‐dependent. EADs from this study were within range of predicted doses from other in vitro and model organism data. Conclusions This study highlights the importance of pharmacokinetic considerations when using in vitro assays and demonstrates the utility of the devTOX qP human stem cell‐based platform to quantitatively assess a chemical's developmental toxicity potency.
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