Lakhani Vinal V, Generaux Grant, Howell Brett A, Longo Diane M, Watkins Paul B
DILIsym Services Inc., A Simulations-Plus Company, Durham, North Carolina, USA.
UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Clin Pharmacol Ther. 2023 Nov;114(5):1006-1014. doi: 10.1002/cpt.3004. Epub 2023 Jul 28.
In clinical trials of cannabidiol (CBD) for the treatment of seizures in patients with Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis complex, elevations in serum alanine aminotransferase (ALT) > 3× the upper limit of normal were observed in some patents, but the incidence was much greater in patients who were receiving treatment with valproate (VPA) before starting CBD. To explore potential mechanisms underlying this interaction, we used DILIsym, a quantitative systems toxicology model, to predict ALT elevations in a simulated human population treated with CBD alone, VPA alone, and when CBD dosing was starting during treatment with VPA. We gathered in vitro data assessing the potential for CBD, the two major CBD metabolites, and VPA to cause hepatotoxicity via inhibition of bile acid transporters, mitochondrial dysfunction, and production of reactive oxygen species (ROS). Physiologically-based pharmacokinetic models for CBD and VPA were used to predict liver exposure. DILIsym simulations predicted dose-dependent ALT elevations from CBD treatment and this was predominantly driven by ROS production from the parent molecule. DILIsym also predicted VPA treatment to cause ALT elevations which were transient when mitochondrial biogenesis was incorporated into the model. Contrary to the clinical experience, simulation of 2 weeks treatment with VPA prior to introduction of CBD treatment did not predict an increase of the incidence of ALT elevations relative to CBD treatment alone. We conclude that the marked increased incidence of CBD-associated ALT elevations in patients already receiving VPA is unlikely to involve the three major mechanisms of direct hepatotoxicity.
在大麻二酚（CBD）治疗德雷维特综合征、伦诺克斯 - 加斯托综合征和结节性硬化症患者癫痫发作的临床试验中，部分患者血清丙氨酸氨基转移酶（ALT）升高超过正常上限的3倍，但在开始使用CBD之前接受丙戊酸（VPA）治疗的患者中，这一发生率要高得多。为了探究这种相互作用背后的潜在机制，我们使用了定量系统毒理学模型DILIsym，来预测在单独使用CBD、单独使用VPA以及在VPA治疗期间开始使用CBD的模拟人群中ALT的升高情况。我们收集了体外数据，评估CBD、两种主要的CBD代谢物和VPA通过抑制胆汁酸转运体、线粒体功能障碍和活性氧（ROS）产生而导致肝毒性的可能性。使用基于生理学的CBD和VPA药代动力学模型来预测肝脏暴露情况。DILIsym模拟预测了CBD治疗导致的剂量依赖性ALT升高，这主要是由母体分子产生的ROS驱动的。DILIsym还预测VPA治疗会导致ALT升高，当将线粒体生物发生纳入模型时，这种升高是短暂的。与临床经验相反，在引入CBD治疗之前先用VPA进行2周治疗的模拟结果并未预测相对于单独使用CBD治疗，ALT升高的发生率会增加。我们得出结论，在已经接受VPA治疗的患者中，与CBD相关的ALT升高发生率显著增加不太可能涉及直接肝毒性的三种主要机制。
