BACKGROUND The mechanistic target of rapamycin inhibitors everolimus and sirolimus have activity against multiple manifestations of tuberous sclerosis complex and are approved to treat astrocytomas, angiomyolipomas, lymphangioleiomyomatosis, and epilepsy. Cannabidiol is a novel antiepileptic medication. There is lack of information regarding drug-drug interactions between mechanistic target of rapamycin inhibitors and cannabidiol in clinical practice. METHODS We reviewed patients with tuberous sclerosis complex who were treated with a mechanistic target of rapamycin inhibitor (everolimus, sirolimus) and cannabidiol. Clinical information, mechanistic target of rapamycin inhibitor and cannabidiol dosing, concomitant antiepileptic drugs, as well as laboratory and adverse events were reviewed before and after initiation of cannabidiol. RESULTS A total of 25 patients were treated with cannabidiol and a mechanistic target of rapamycin inhibitor (18 everolimus, seven sirolimus). All mechanistic target of rapamycin inhibitor levels were drawn as troughs. Levels were significantly higher in 76% patients after cannabidiol treatment (P = 0.0003). Median change from baseline was +9.8 ng/mL for everolimus and +5.1 ng/mL for sirolimus. Adverse events occurred in 40%, with diarrhea being the most frequent adverse event occurring in three patients. No severe adverse events occurred during the treatment period. CONCLUSIONS Cannabidiol resulted in increased serum levels of everolimus and/or sirolimus. Some patients experienced doubling or tripling of their mechanistic target of rapamycin inhibitor trough following the addition of cannabidiol. In some cases, this resulted in clinical toxicity, as well as laboratory abnormalities. Awareness of this interaction can lead clinicians to evaluate serum levels and other safety laboratory studies more closely, and thereby avoid potentially significant adverse effects. In patients known to be prone to mechanistic target of rapamycin inhibitor toxicity, preemptive reduction in dose may be warranted upon initiation of cannabidiol.

中文翻译：

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卡那比二醇可提高结节性硬化症患者雷帕霉素抑制剂水平的机制靶点。

背景技术雷帕霉素抑制剂依维莫司和西罗莫司的机械靶标对结节性硬化症的多种表现具有活性，并被批准用于治疗星形细胞瘤，血管平滑肌脂肪瘤，淋巴管平滑肌瘤病和癫痫病。卡那比二醇是一种新型的抗癫痫药。在临床实践中，缺乏有关雷帕霉素抑制剂的作用靶标与大麻二酚之间的药物相互作用的信息。方法我们回顾了患有结节性硬化症的患者，这些患者接受了雷帕霉素抑制剂（依维莫司，西罗莫司）和大麻二酚的机械靶向治疗。在开始使用大麻素之前和之后，回顾了雷帕霉素抑制剂和大麻素剂量的作用靶点，并用的抗癫痫药，实验室检查和不良事件的临床信息。结果共有25例患者接受了大麻素和雷帕霉素抑制剂（18个依维莫司，7个西罗莫司）的机械作用靶点治疗。雷帕霉素抑制剂水平的所有机械目标均绘制为低谷。大麻素治疗后76％的患者的水平显着更高（P = 0.0003）。依维莫司从基线的中位变化为+9.8 ng / mL，西罗莫司为+5.1 ng / mL。不良事件发生率为40％，腹泻是三位患者中最常见的不良事件。在治疗期间没有发生严重的不良事件。结论卡那比二醇导致依维莫司和/或西罗莫司的血清水平升高。添加大麻素后，一些患者的雷帕霉素抑制剂谷机制靶点倍增或三倍。在某些情况下，这导致了临床毒性以及实验室异常。意识到这种相互作用可以使临床医生更紧密地评估血清水平和其他安全实验室研究，从而避免潜在的重大不利影响。在已知容易发生雷帕霉素抑制剂毒性的机械靶标的患者中，在开始使用大麻二酚时可能需要提前减少剂量。