Institute of Clinical Pharmacology and Toxicology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, Berlin Institute of Health, Berlin, Germany.
Istituto Superiore Di Sanità, Environment and Health Department, Mechanisms, Biomarkers and Models Unit, Rome, Italy.
Arch Toxicol. 2021 Apr;95(4):1433-1442. doi: 10.1007/s00204-021-02989-2. Epub 2021 Feb 19.
Amiodarone is an antiarrhythmic agent inducing adverse effects on the nervous system, among others. We applied physiologically based pharmacokinetic (PBPK) modeling combined with benchmark dose modeling to predict, based on published in vitro data, the in vivo dose of amiodarone which may lead to adverse neurological effects in patients. We performed in vitro-in vivo extrapolation (IVIVE) from concentrations measured in the cell lysate of a rat brain 3D cell model using a validated human PBPK model. Among the observed in vitro effects, inhibition of choline acetyl transferase (ChAT) was selected as a marker for neurotoxicity. By reverse dosimetry, we transformed the in vitro concentration-effect relationship into in vivo effective human doses, using the calculated in vitro area under the curve (AUC) of amiodarone as the pharmacokinetic metric. The upper benchmark dose (BMDU) was calculated and compared with clinical doses eliciting neurological adverse effects in patients. The AUCs in the in vitro brain cell culture after 14-day repeated dosing of nominal concentration equal to 1.25 and 2.5 µM amiodarone were 1.00 and 1.99 µg*h/mL, respectively. The BMDU was 385.4 mg for intravenous converted to 593 mg for oral application using the bioavailability factor of 0.65 as reported in the literature. The predicted dose compares well with neurotoxic doses in patients supporting the hypothesis that impaired ChAT activity may be related to the molecular/cellular mechanisms of amiodarone neurotoxicity. Our study shows that predicting effects from in vitro data together with IVIVE can be used at the initial stage for the evaluation of potential adverse drug reactions and safety assessment in humans.
胺碘酮是一种抗心律失常药物，会对神经系统等产生不良反应。我们应用基于生理学的药代动力学（PBPK）模型结合基准剂量建模，根据已发表的体外数据预测可能导致患者出现不良神经作用的胺碘酮体内剂量。我们使用经过验证的人体 PBPK 模型，对大鼠脑 3D 细胞模型细胞裂解物中测量的浓度进行了体外-体内外推（IVIVE）。在观察到的体外作用中，选择胆碱乙酰转移酶（ChAT）抑制作为神经毒性的标志物。通过反向剂量测定，我们将体外浓度-效应关系转化为体内有效的人体剂量，使用计算出的胺碘酮体外 AUC 作为药代动力学指标。计算并比较了计算得出的体外脑细胞培养中 14 天重复给药后 1.25 和 2.5µM 胺碘酮的 AUC 分别为 1.00 和 1.99µg*h/mL。BMDU 为 385.4mg，静脉给药转换为口服给药时，采用文献报道的生物利用度因子 0.65，BMDU 为 593mg。预测剂量与患者的神经毒性剂量相当，支持 ChAT 活性受损可能与胺碘酮神经毒性的分子/细胞机制有关的假说。我们的研究表明，将体外数据预测与 IVIVE 相结合，可以在药物不良反应评估和人体安全性评估的初始阶段用于预测。
