DILIsym Services division, Simulations Plus, Inc., Durham, North Carolina, USA.
Eshelman School of Pharmacy, Institute for Drug Safety Sciences, University of North Carolina, Chapel Hill, North Carolina, USA.
Clin Pharmacol Ther. 2023 Nov;114(5):1023-1032. doi: 10.1002/cpt.3010. Epub 2023 Aug 10.
BAY1128688 is a selective inhibitor of AKR1C3, investigated recently in a trial that was prematurely terminated due to drug-induced liver injury. These unexpected observations prompted use of the quantitative systems toxicology model, DILIsym, to determine possible mechanisms of hepatotoxicity. Using mechanistic in vitro toxicity data as well as clinical exposure data, DILIsym predicted the potential for BAY1128688 to cause liver toxicity (elevations in serum alanine aminotransferase (ALT)) and elevations in serum bilirubin. Initial simulations overpredicted hepatotoxicity and bilirubin elevations, so the BAY1128688 representation within DILIsym underwent optimization. The liver partition coefficient K was altered to align simulated bilirubin elevations with those observed clinically. Altering the mode of bile acid canalicular and basolateral efflux inhibition was necessary to accurately predict ALT elevations. Optimization results support that bilirubin elevations observed early during treatment are due to altered bilirubin metabolism and transporter inhibition, which is independent of liver injury. The modeling further supports that on-treatment ALT elevations result from inhibition of bile acid transporters, particularly the bile salt excretory pump, leading to accumulation of toxic bile acids. The predicted dose-dependent intrinsic hepatotoxicity may increase patient susceptibility to an adaptive immune response, accounting for ALT elevations observed after completion of treatment. These BAY1128688 simulations provide insight into the mechanisms behind hepatotoxicity and bilirubin elevations and may inform the potential risk posed by future compounds.
BAY1128688 是 AKR1C3 的选择性抑制剂，最近在一项因药物性肝损伤而提前终止的试验中进行了研究。这些意外观察结果促使使用定量系统毒理学模型 DILIsym 来确定肝毒性的可能机制。利用机制体外毒性数据和临床暴露数据，DILIsym 预测了 BAY1128688 引起肝毒性（血清丙氨酸氨基转移酶 (ALT) 升高）和血清胆红素升高的潜力。初步模拟高估了肝毒性和胆红素升高，因此对 DILIsym 中的 BAY1128688 表示进行了优化。改变了肝分配系数 K，以使模拟的胆红素升高与临床观察到的相符。改变胆酸管腔和基底外侧外排抑制的模式对于准确预测 ALT 升高是必要的。优化结果支持在治疗早期观察到的胆红素升高是由于胆红素代谢和转运蛋白抑制的改变，这与肝损伤无关。该模型进一步支持治疗期间 ALT 升高是由于胆汁酸转运蛋白的抑制，特别是胆汁盐排泄泵，导致毒性胆汁酸的积累。预测的剂量依赖性固有肝毒性可能会增加患者对适应性免疫反应的敏感性，从而解释了治疗完成后观察到的 ALT 升高。这些 BAY1128688 模拟提供了对肝毒性和胆红素升高背后机制的深入了解，并可能为未来化合物的潜在风险提供信息。
