In vitro to in vivo extrapolation and species response comparisons for drug-induced liver injury (DILI) using DILIsym™: a mechanistic, mathematical model of DILI
In vitro to in vivo extrapolation and species response comparisons for drug-induced liver injury (DILI) using DILIsym™: a mechanistic, mathematical model of DILI
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DOI：
10.1007/s10928-012-9266-0
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发表时间：
2012-10-01
影响因子：
2.5
通讯作者：
Watkins, Paul B.
中科院分区：
文献类型：
--
作者：
Howell, Brett A.;Yang, Yuching;Watkins, Paul B.
药物性肝损伤（DILI）不仅是所有需要药物治疗的患者的主要关注点，也是制药行业的主要关注点。许多新的体外测定和临床前动物模型正在开发中，以帮助筛选可能导致 DILI 的化合物。这项研究表明，机械数学模型提供了一种解释和推断结果的方法。 DILIsym (TM) 模型（版本 1A）是 DILI 的数学表示，与肝毒性药物甲芘林 (MP) 模型的体外数据相结合，进行体外到体内的外推。此外，比较不同物种 DILI 反应的模拟说明了建模如何帮助选择最合适的临床前物种，以获得与人类相关的安全测试结果。用于预测 MP DILI 的参数输入仅限于仅与 ADME（吸收、分布、代谢、消除）过程相关的体外输入。 MP 毒性被正确预测发生在大鼠身上，但在人类和小鼠的模拟中并不明显（与文献一致）。当在同等剂量下比较 MP 和对乙酰氨基酚 (APAP) 在大鼠、小鼠和人类之间的肝毒性时，最容易受到 APAP 影响的物种对 MP 不敏感，反之亦然。此外，考虑模拟群体样本（SimPops (TM)）的变异性为预测提供了信心，并允许检查最能预测结果的生物参数。模型对参数敏感性的差异与物种差异有关，但每种药物/物种组合的 DILI 严重程度也是一个重要因素。
Drug-induced liver injury (DILI) is not only a major concern for all patients requiring drug therapy, but also for the pharmaceutical industry. Many new in vitro assays and pre-clinical animal models are being developed to help screen compounds for the potential to cause DILI. This study demonstrates that mechanistic, mathematical modeling offers a method for interpreting and extrapolating results. The DILIsym (TM) model (version 1A), a mathematical representation of DILI, was combined with in vitro data for the model hepatotoxicant methapyrilene (MP) to carry out an in vitro to in vivo extrapolation. In addition, simulations comparing DILI responses across species illustrated how modeling can aid in selecting the most appropriate pre-clinical species for safety testing results relevant to humans. The parameter inputs used to predict DILI for MP were restricted to in vitro inputs solely related to ADME (absorption, distribution, metabolism, elimination) processes. MP toxicity was correctly predicted to occur in rats, but was not apparent in the simulations for humans and mice (consistent with literature). When the hepatotoxicity of MP and acetaminophen (APAP) was compared across rats, mice, and humans at an equivalent dose, the species most susceptible to APAP was not susceptible to MP, and vice versa. Furthermore, consideration of variability in simulated population samples (SimPops (TM)) provided confidence in the predictions and allowed examination of the biological parameters most predictive of outcome. Differences in model sensitivity to the parameters were related to species differences, but the severity of DILI for each drug/species combination was also an important factor.