Valproic Acid

摘要：药物性肝损伤（DILI）是药物研发失败和已批准药物退出市场的主要原因，因此对准确预测肝毒性体外检测方法的需求日益迫切。然而，肝细胞的二维细胞培养体系由于无法准确模拟和重现体内肝细胞的真实环境及微生态系统，不适合长期服用药物的毒性研究。鉴于此，在药物开发和活性化合物安全性评价中，亟需具备更高预测性的肝脏模型来评估药物的肝毒性。本文综述了体外DILI肝细胞三维培养系统的构建和应用，为其在DILI分析中的有效实施提供参考。  关键词：化学性与药物性肝损伤；模型，生物学；细胞培养技术        药物性肝损伤（drug-induced liver injury，DILI）是一种常见的肝脏疾病，是指由化学药品、生物制品、中成药等处方药或非处方药，以及中药材、天然药物、保健品、膳食补充剂等产品，或其代谢产物、辅料、污染物、杂质等引发的肝损伤［1］。DILI在易感人群中发生，受遗传和环境因素影响。这些因素可能会影响药物的代谢和/或排泄过程，进而引发一系列细胞层面的反应［2］。不同国家DILI的发病率有所差异：法国一项基于人群的前瞻性研究通过系统收集新发DILI病例，估算出一般人群年发病率约为14/10万，该数据为法国监管机构自发报告病例数的16倍［3］；而中国的DILI发病率约为23.8/10万［4］。DILI是临床前研究和临床研究中药物研发失败率较高的原因之一，也是药物上市后不良反应的重要诱因［5］。研究表明，DILI仍是美国和欧洲急性肝功能衰竭的常见病因［5］，因此亟需建立肝损伤评估模型以预测药物治疗可能导致的肝损伤风险。在进入临床试验前，药物安全性需在动物模型中评估，但38%～51%具有肝毒性倾向的化合物在临床前试验中未被检出［5-6］；同时，使用实验动物存在诸多不便，包括物种间的生物学差异、敏感性差异、使用成本高昂及动物福利等限制［6-8］。另有研究证实，人类细胞系在预测人类致死峰值浓度方面优于动物细胞培养系统，为人类细胞模型在毒性研究中的应用奠定基础。在单层二维培养（second-dimensional cell culture，SDCC）体系中生长的原代肝细胞（primary hepatocyte，PH）易于使用，但在仅能检测急性药物诱导毒性的标准培养条件下，包括药物代谢在内的肝脏特异性功能会迅速下降。因此，研究人员对PH模型进行诸多改进，以完善肝细胞功能及微生态，例如在Ⅰ/Ⅳ型胶原、纤连蛋白或其他细胞外基质包被的平板中培养细胞，或在2层Ⅰ型胶原及基质胶之间进行三维细胞培养（three dimensional cell culture，TDCC）［9］。        本文将系统阐述DILI的分类、发病机制，以及不同人类肝细胞系统在三维（3D）培养技术中的应用和性能。 １BDILI概述  1.1 DILI分类　根据发病机制，DILI可分为固有型、特异质型和间接型。其中，固有型DILI由药物或其代谢产物对肝脏的直接毒性造成，与剂量相关，当达到一定剂量阈值或暴露水平时个体可发生肝损伤，且具有可预测的特点，常见的相关药物包括对乙酰氨基酚（APAP）、阿司匹林和可卡因等［10］；特异质型DILI仅发生于少数药物暴露人群，通常与剂量无关，且无法根据已知的药理作用预测，其发生主要与独特的宿主特征相关，因高发病率、高死亡率及不可预测性，已成为重大的临床挑战［11-12］；间接型DILI则是部分药物通过加重原有肝脏疾病或改变患者的免疫系统状态间接引发的肝损伤［12］。 1.2 DILI 发病机制　DILI的发病机制尚未完全明确［13］。母体药物本身或其在肝脏代谢过程中产生的代谢物均可导致DILI，药物或其代谢物诱导的多种细胞内化学损伤与DILI易感性相关［14］。一方面，药物转运蛋白和代谢酶在肝脏反应性代谢物的清除中发挥重要作用，肝毒性可能与药物代谢过程有关，尤其是Ⅰ期代谢酶如CYP（细胞色素P450）的氧化作用；另一方面，药物生化过程中活性氧的产生与细胞通过酶促抗氧化剂清除活性氧能力的失衡（即氧化应激），会因接触毒物导致产生过量的活性氧，进而损伤肝细胞的关键成分［14］。在早期临床前阶段，优选药物的功能性和体外平台必须反映体内肝脏环境的复杂性。因此，在开发体外肝模型时，应考虑肝细胞来源和培养系统。SDCC作为研究细胞对化合物反应的常规体外方法，具有成本低和操作简便的优点。在该系统中，细胞在硬质平面上水平扩散生长，呈现非自然立体增殖的平面形态。与体内肝细胞真实环境相比，SDCC在细胞形态、功能和行为方面均存在明显差异［6］，且PH会迅速失去活力、表型及肝脏特异性功能［3］。因此，SDCC体系无法模拟肝细胞在体内的自然增殖，基于该体系的药物试验难以准确反映体内肝细胞的真实情况。        针对SDCC存在的问题，众多研究团队致力于开发更复杂且与生理相关的TDCC系统，其能保留细胞的自然形态和生长状态，促进细胞良好分化。在TDCC模型中，细胞可通过离子、小分子和电子交换实现相互通信。此外，TDCC中的细胞通常对药物治疗表现出更强的耐受性，其药物代谢过程能够准确反映药物的作用机制，从而更好地模拟细胞间及细胞与基质间的相互作用［15-16］。肝细胞TDCC技术旨在维持或改善原代肝脏特性，为毒理学分析提供了有效的工具［17］。 ２TDCC常用细胞         肝脏由多种功能各异的细胞构成，这些细胞通过旁分泌和自分泌信号进行交流与协作，其中肝细胞、肝星状细胞、肝窦内皮细胞及Kupffer细胞是执行肝脏基本功能的主要细胞类型［18］。在体外重建肝组织的研究中，常用的细胞系包括新鲜及冷冻保存的原代人肝细胞、永生化细胞系和干细胞衍生细胞系等［19］。  2.1 PH 肝细胞占肝内细胞总数的80%，几乎承担与肝脏代谢相关的所有功能。在组织工程中，从肝脏中直接分离获得的肝细胞被称为PH，其来源包括人和动物［18，20］。作为构建人类肝脏体外模型的“金标准”，PH的分泌特性与代谢酶活性和体内肝细胞一致，能可靠反映体内肝脏特性，因此更适合药物和代谢毒性的研究［21-24］。研究表明，在胶原蛋白夹心培养物中培养人PH可增强能量代谢的基因表达，并部分提升CYP酶活性［25］；在三明治肝细胞培养模型中，CYP3A活性受到抑制［26］，且五味子提取物能抑制CYP3A4/5的活性并提升CYP3A4 mRNA水平［27］。然而，PH也存在局限性，其获取流程较为复杂，分离方法的差异可能导致实验结果不一致，且悬浮培养时间短，易出现功能和形态丧失［28］。  2.2 永生化细胞系　永生化细胞系如HepG2、HepaRG、Hep3B等，在毒理学研究中应用广泛。这些细胞具有无限增殖的能力，易于操纵且表型稳定，在药物代谢和毒性反应中表现良好［19］。与PH相比，永生化细胞系可避免供应受限、肝细胞表型早期变化及供体间的高变异性等问题［29］，其主要缺点为关键药物代谢酶表达不足［23］。Choi等［30］开发了一种使用HepG2细胞与人肝微粒体结合的体外模型，用于预测环磷酰胺代谢物的毒性；Xu等［31］研究发现，使用谷胱甘肽耗尽的HepaRG细胞进行毒性测试，可提高DILI风险的可预测性。  2.3 干细胞源性肝细胞　近年来，干细胞衍生的肝类器官主要由肝祖细胞、人胚胎干细胞、富含亮氨酸的重复序列G蛋白偶联受体5阳性的成体干细胞及诱导多能干细胞（induced pluripotent stem cell，iPSC）［32］组成。这些细胞具有无限复制的潜力，可分化为多种人体细胞类型，且能转化为与正常肝细胞功能高度相似的功能性肝细胞，同时保持遗传稳定性［22-23］。通过比较肝毒性和非肝毒性模型化合物在人胚胎干细胞衍生的肝细胞和人PH中的毒性差异，证实从人胚胎干细胞和iPSC分化的肝细胞样细胞可准确预测人类肝毒性，并能根据其细胞毒性、半胱天冬酶依赖性凋亡或坏死机制对所测化合物的肝毒性进行分类［33］。 3 用于DILI的TDCC类型         TDCC模型可分为基于支架的模型、无支架模型和混合系统［28］。  3.1 有支架型TDCC　在支架TDCC中，高分子材料为细胞提供立体架构，使细胞能够在网络框架中生长，其中水凝胶是较常用的材料。水凝胶中含有丰富的可溶性生长因子，可维持细胞较高的生物活性；同时，其具有三维结构、亲水性和聚合物网络，能够模拟类似于天然组织细胞外基质的柔软湿润环境，促进氧气、营养物质、废物和可溶性因子的运输［6］，且高含水量、柔软结构和孔隙率使其与活组织高度相似［33］。        水凝胶由聚合物链交联形成，根据聚合物来源可分为天然、合成及半合成聚合物水凝胶。其中，天然水凝胶包括纤维素、壳聚糖等，具有固有的生物相容性、生物活性和生物降解性，但稳定性和机械强度较弱；合成水凝胶具有较高的稳定性和机械强度；半合成水凝胶通过对天然聚合物进行化学改性或将其与合成聚合物复合制备［34-35］。       水凝胶可采用生物或合成材料进行设计，模拟天然细胞外基质的多种特征，提供可调控且稳定的环境。此外，合成水凝胶还可与有机成分结合形成混合水凝胶，进一步优化其性能［35］。例如，基于FEFEFKFK（F，苯丙氨酸；E，谷酰基；K，赖氨酰基）的FEK-SAPH（自组装肽水凝胶）培养大鼠PH 14d后，胆管网络形成，白蛋白和尿素分泌显著增加，胆道外排转运体胆盐输出泵的表达量明显升高，表明该水凝胶体系可用于评估药物在肝细胞中的吸收、分布、代谢和排泄过程［36］；热响应泊洛沙姆/海藻酸盐半合成水凝胶用于生物打印3D肝脏构建物时，三维HepG2球体中CYP1A2的mRNA表达水平较二维培养物更高［37］。  3.2 无支架型TDCC　  3.2.1 悬滴型TDCC　悬滴培养法是一种将少量细胞悬液加入特殊微量滴定板孔的模型构建方法，利用表面张力使液滴保持在原位并呈悬挂状态，同时在重力作用下使细胞集中于液滴底部。在此条件下，细胞自发聚集并形成球状体。由于液滴位于疏水表面，球状体能稳定形成且不会黏附于基质［38-43］。该技术操作相对简单，可获得大量均匀球体，且效率较高。与松散的细胞聚集体相比，紧密堆积的球状体更易形成，但其形态会受细胞类型影响［43］。        在DILI研究中，悬滴模型应用广泛。其优势在于能将培养的球体高通量移植至其他平台，便于使用接触式方法进行后续分析［44］。Mueller等［45］基于悬滴系统制作HepaRG和HepG2细胞的3D球体，评估具有不同毒性机制的4种药物（黄曲霉毒素B1、胺碘酮、丙戊酸和氯丙嗪）的急性毒性，结果表明3D HepaRG培养物对黄曲霉毒素B1的敏感性高于其他测试培养物，且其CYP3A4活性更高。另有研究构建的悬滴模型可维持高通量、长期的3D器官型培养系统，与SDCC相比，该模型中白蛋白、尿素、葡萄糖等的产量均呈增加趋势，且TDCC中CYP2E1活性始终高于SDCC［29］。  3.2.2 微流控型TDCC　微流控3D培养系统主要由微气动系统（如液体泵、气阀等）和微流体结构（芯片）组成［39-40］。软光刻作为基于印刷、成型和浮雕的微纳米结构制造方法，是目前微流体器件的主流制造技术，其中PDMS（聚二甲基硅氧烷）因具备透气性、良好的生化稳定性和无毒性，成为常用材料之一［46］。微流控细胞培养系统可通过控制时空参数（如细胞-细胞和细胞-基质相互作用）来模拟细胞微环境，而基于微流体的灌注细胞培养系统可提供与生理相关的条件，维持细胞的体内样表型和生物活性［36］。         微流控肝脏生物芯片被用于评估氟替卡松的毒性，结合转录组学谱分析发现，氟替卡松在低浓度下可引起促细胞存活反应，较高浓度则导致细胞坏死［47］；3D HepaTox芯片采用在多路复用、区室化的微流体通道中培养大鼠肝细胞，与夹心培养物相比，该模型有效延长CYP1A1/2、UGT（UDP-葡萄糖醛酸转移酶）活性及白蛋白分泌的维持时间，最长可达3d［48］。  3.2.3 类器官TDCC　尽管肝癌及其细胞系可无限增殖，但具有癌性特征，缺乏正常肝细胞的关键功能。近年来，类器官作为一种新型生理模型系统，被广泛应用于多种器官和组织的研究，其显著优势如下：可从健康和病变组织中生成，能长期扩增并保持遗传稳定性，还可通过冷冻保存建立生物库［49-50］。类器官能够模仿人体细胞和器官的组成与功能，且仅需少量组织活检即可获得，为建立模拟人体组织特征的高通量筛选模型提供了重要基础［51］。类器官通常由组织来源的原代细胞、祖细胞、胚胎干细胞或iPSC产生［52］。相关研究中，源自iPSC的人肝类器官被用于评估3种肝毒性物质和3种非肝毒性化合物的毒性，结果准确反映了这6种物质的实际毒性［53］；源自人类多能干细胞的人肝类器官和HepG2球体经不同浓度的APAP处理后，人肝类器官对APAP诱导的毒性更敏感［54］。  3.2.4　生物打印TDCC　近年来，3D打印技术发展迅速，其中3D生物打印作为前沿领域，以细胞和生物材料为生物墨水，根据预设计精确控制细胞及其微环境的空间布局，最大限度模拟体内真实环境，为体外肝细胞试验提供了新的可能性［54-56］。该技术主要包括喷墨生物打印、光固化生物打印和挤出式生物打印［57］。同时，3D生物打印可用于模拟肝脏功能，可更好地满足研究需求［56］。例如，将封装于水凝胶支架的肝球体生物打印至微流体装置，构建一种有助于肝毒性测试的肝组织模型，经急性毒性剂量的APAP连续暴露超过1周后，含有APAP的培养物在6d内代谢活性显著降低，与实际结果一致［58］；实质肝细胞、肝星状细胞和人脐静脉内皮细胞的生物打印人肝组织模拟物，在3D培养中形成内皮细胞网络和细胞外基质，呈现组织样结构，且具有稳定的活力、功能和CYP450酶活性，进一步缩短与真实组织的差异［59］。 4 小结与展望        近年来，体外肝细胞模型取得了显著进展，为3R原则（替代、减少、优化）实施提供了重要的支持［60］。肝脏的药物代谢、转运和药物相互作用是药物研发的核心研究内容，而基于肝细胞或非实质细胞共培养的微系统，可在药物研发早期预测其肝脏效应，成为评价药物毒性潜力和DILI机制的重要工具。研究表明，当在3D模型中培养相同细胞时，这些细胞的表型与体内肝细胞更接近，且去分化过程得以延迟；同时，3D培养稳定表达的性能支持重复给药方案，便于慢性药物诱导的毒性评价［61-62］。目前，复杂肝脏疾病（如胆汁淤积、脂肪变性、纤维化和肝炎）可在体外构建细胞模型，为药物靶点验证及药物作用和毒性机制提供研究平台。因此，生物学变异的体外系统开发可以更好地预测体内药物反应。体外模型的未来发展前沿之一是与免疫系统共同作用，有望在个体间差异研究和化学损 伤的特异质反应方面实现重大突破。免疫细胞与肝细胞共培养体系，将获得肝细胞单一培养物无法模拟的肝毒素作用模式［48］。        然而，TDCC模型仍存在诸多局限性，虽然TDCC模型更接近体内生理条件，但培养环境的调控需求更高，以便更准确地复现体内微环境［63］。监测技术匮乏限制了模型的进一步发展，针对3D培养的监测技术将助力模型的推广实施与标准化［64］。此外，有限的渗透性会影响细胞活力和功能，导致难以建立适用于高通量筛选的精确自动化系统；TDCC模型由静止、非分裂、完全分化的细胞构成，而遗传毒性评估需依赖活跃的分裂细胞，这一特性限制了其在遗传毒性评估中的应用。同时，细胞体外存活时间有限是细胞培养模型作为DILI检测的主要挑战，导致现有模型仅适用于急性毒性测试。尽管3D模型中细胞存活时间得以延长，但存活时间问题仍然存在［14］。3D共培养模型还面临成本高、小型模型中液体自动化处理难度大等局限［16，65-66］。未来需通过多学科交叉合作，开发更精准的技术，推动3D共培养技术的成熟与完善。 引证本文 李子婷,张珂,赵锋,等.三维肝细胞模型在药物性肝损伤中的应用[J].临床肝胆病杂志,2025,41(9):1931-1936.

New interim results from the EpiCom trial, a prospective evaluation of behavioral outcomes in patients with tuberous sclerosis complex, suggest improvements in non-seizure outcomes Eight abstracts, including four late-breaking abstracts, underscore Jazz's continued commitment to the epilepsy community and advancing the comprehensive treatment for rare forms of epilepsy For U.S. media and investors only DUBLIN , Dec. 5, 2025 /PRNewswire/ -- Jazz Pharmaceuticals plc (Nasdaq: JAZZ) today announced that eight abstracts, including four that are late-breaking, will be presented on Epidiolex® (cannabidiol) at the American Epilepsy Society (AES) 2025 Annual Meeting, being held December 5-9, 2025 , in Atlanta, Georgia . Notable data include new results from the EpiCom trial, an ongoing Phase 3b/4 study evaluating behavioral and other non-seizure outcomes after initiation of adjunctive Epidiolex treatment in participants with tuberous sclerosis complex (TSC)-associated seizures. Notably, the prespecified 6-month intermediate analysis of EpiCom demonstrated promising reductions in the TSC–Associated Neuropsychiatric Disorders Self-Report Quantified Checklist (TAND-SQ) and Aberrant Behavior Checklist (ABC) subscale scores, as well as in the severity of behavioral problems reported by caregivers and clinicians after 26 weeks of Epidiolex treatment. "We are proud to share extensive research at AES 2025, including findings from the innovative EpiCom trial which utilized novel endpoints focused on individualized outcomes, including each participant's respective most problematic behavior as identified by caregivers and clinicians to ensure our research addresses the priorities of those we serve," said Jessa Alexander , Ph.D., neuroscience therapeutic area head, global medical and scientific affairs of Jazz Pharmaceuticals . "Data from EpiCom and real-world insights continue to expand our understanding of the complex realities faced by patients living with rare epilepsy disorders while further underscoring Epidiolex's ability to contribute to meaningful, holistic management." Additional highlights at AES 2025 include: A late-breaking poster featuring results from a Phase 1 clinical study evaluating bidirectional pharmacokinetic (PK) drug-drug interactions between Epidiolex and cenobamate, which did not find PK interactions between cannabidiol and cenobamate parent molecules when concomitantly administered at clinically relevant dosages. A late-breaking poster showcasing preclinical data that demonstrates a novel synergistic pharmacodynamic interaction between Epidiolex and cenobamate in effectiveness in the mouse maximal electroshock seizure model of acute generalized seizures. Two presentations highlight real-world effectiveness of Epidiolex using data from the U.S. Optum® Market Clarity Database (an integrated electronic health record and claims database). One late-breaking poster features data that shows Epidiolex initiation in CBD-naïve patients with Dravet Syndrome (DS), LGS or TSC is associated with reduced polypharmacy and healthcare resource utilization (HCRU) at 12 months, with further reductions among early-line Epidiolex initiators. The other poster highlights data that indicates Epidiolex initiation also reduces antiseizure medication cycling at 12 months, as well as decreased polypharmacy and HCRU in both pediatric and adult patients. A poster presentation featuring post-hoc analysis from the Expanded Access Program demonstrates Epidiolex treatment is associated with reductions in convulsive and total seizure frequency in patients with developmental and epileptic encephalopathies (DEEs) and rare epilepsy syndromes. The comparative effectiveness analysis confirms the superiority of Epidiolex in reducing seizure frequency from baseline compared to an external placebo control arm. A poster presentation highlighting a subgroup analysis of Epidiolex pivotal clinical trial data showing participants with Lennox-Gastaut syndrome (LGS) diagnoses, which are secondary to a genetic DEE, experienced consistent efficacy and safety as compared to the overall LGS pivotal trial populations. A late-breaking poster presentation on data from the Epilepsy Learning Healthcare System (ELHS), an Epilepsy Foundation -sponsored initiative, highlights its potential to provide real-world treatment insights beyond clinical trials and claims data. All AES 2025 abstracts are available online at the following link: aesnet.org/education/annual-meeting/aes-abstract-search. A full list of Jazz Pharmaceuticals' presentations follows below: Presentation Title Presenting Author Poster Details | Date & Time (ET) Cannabidiol Efficacy in Patients With Lennox-Gastaut Syndrome With Developmental and Epileptic Encephalopathy-Associated Genetic Variants: A Subgroup Analysis E Thiele Poster Number: 1.382 Session Date/Time: Saturday December 6 , 12:00-2:00pm Phase 1, Open-Label, Fixed-Sequence, Bidirectional, Pharmacokinetic Drug-Drug Interaction Study Between Cannabidiol and Cenobamate in Healthy Adult Participants A Vijan Poster Number: 1.545 Session Date/Time: Saturday December 6 , 12:00-2:00pm An Assessment of Acute Pharmacodynamic Drug-Drug Interactions Between Cannabidiol and Cenobamate in a Mouse Model of Generalized Tonic Seizures W Hind Poster Number: 1.546 Session Date/Time: Saturday December 6 , 12:00-2:00pm A Population Health Study of Patients Prescribed Cannabidiol in the Epilepsy Learning Healthcare System (ELHS) Registry KM Farrell Poster Number: 1.549 Session Date/Time: Saturday December 6 , 12:00-2:00pm Effectiveness of Cannabidiol in Patients With Rare Epilepsies Compared to External Placebo Control: A Post-Hoc Analysis From the Expanded Access Program Y Park Poster Number: 2.337 Session Date/Time: Sunday December 7 , 12:00-2:00pm Real-World Polypharmacy and Healthcare Resource Utilization After Early-Line Treatment With Cannabidiol for Lennox-Gastaut Syndrome, Dravet Syndrome, and Tuberous Sclerosis Complex M Navetta Poster Number: 2.433 Session Date/Time: Sunday December 7 , 12:00-2:00pm Tuberous Sclerosis Complex (TSC)–Associated Neuropsychiatric Disorders (TAND) Outcomes Following Adjunctive Cannabidiol (CBD) Treatment: 6-Month Intermediate Analysis of the EpiCom Trial J Stevens Poster Number: 3.351 Session Date/Time: Monday December 8 , 12:00-1:45pm Real-World Effectiveness of Cannabidiol on Antiseizure Medication Cycling, Polypharmacy, and Healthcare Resource Utilization: A US Claims Analysis A Sillah Poster Number: 3.368 Session Date/Time: Monday December 8 , 12:00-1:45pm About Tuberous Sclerosis Complex Tuberous sclerosis complex (TSC) is a rare genetic condition.1 The condition causes mostly benign tumors to grow in vital organs of the body including the brain, skin, heart, eyes, kidneys and lungs2 and is a leading cause of genetic epilepsy.3 People with TSC may experience a variety of seizure types. One of the most common is infantile spasms that typically present in the first year of life; focal (or partial) seizures are also very common.4 TSC is associated with an increased risk of autism and intellectual disability5 and the severity of the condition can vary widely. In some children the disease is very mild, while others may experience life-threatening complications.4 Epilepsy is present in about 85% of patients with TSC and may progress to become intractable to medication.4,6,7 More than 60% of individuals with TSC do not achieve seizure control8 with standard treatments such as antiepileptic drugs, epilepsy surgery, ketogenic diet, or vagus nerve stimulation8 compared to 30%-40% of individuals with epilepsy who do not have TSC who are drug resistant.9,10 About Dravet SyndromeDravet syndrome (DS) is a rare genetic condition that appears during the first year of life with frequent fever-related seizures (febrile seizures). Later, other types of seizures typically arise, including myoclonic seizures (involuntary muscle spasms).11 Additionally, status epilepticus, a potentially life-threatening state of continuous seizure activity requiring emergency medical care, may occur. Children with DS typically experience poor development of language and motor skills, hyperactivity and difficulty relating to others. About Lennox-Gastaut SyndromeLennox-Gastaut syndrome (LGS) begins in childhood. It is characterized by multiple types of seizures. People with LGS begin having frequent seizures in early childhood, usually between ages 3 and 5.12 More than three-quarters of affected individuals have tonic seizures, which cause the muscles to contract uncontrollably. Almost all children with LGS develop learning problems and intellectual disability. Many also have delayed development of motor skills such as sitting and crawling. Most people with LGS require help with usual activities of daily living. About Epidiolex®/Epidyolex® (cannabidiol)Epidiolex/Epidyolex is a prescription, plant-derived cannabis-based medicine administered as an oral solution which contains highly purified cannabidiol (CBD). Cannabidiol, the active ingredient in Epidiolex, is a cannabinoid that naturally occurs in the Cannabis sativa L. plant. The precise mechanisms by which Epidiolex exerts its anticonvulsant effect in humans are unknown. Epidiolex was approved by the U.S. Food and Drug Administration (FDA) for use in the U.S. , the European Commission (EC) for use in Europe , the Medicines and Healthcare products Regulatory Agency (MHRA) for use in Great Britain , the Therapeutic Goods Administration for use in Australia , Swissmedic for use in Switzerland , the Food & Nutrition Services of the Israel Ministry of Health for use in Israel , and the New Zealand Medicines and Medical Devices Safety Authority for use in New Zealand , is an oral solution which contains highly purified cannabidiol (CBD). In the U.S. , Epidiolex is indicated for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS) or tuberous sclerosis complex (TSC) in patients one year of age and older. Epidiolex has received approval in the European Union under the tradename Epidyolex for adjunctive use in conjunction with clobazam to treat seizures associated with LGS and DS in patients two years and older, and for adjunctive use to treat seizures associated with TSC, in patients two years of age and older. Epidiolex has received Orphan Drug Designation (ODD) from the U.S. FDA for the treatment of seizures associated with LGS, DS, and TSC. Similarly, Epidyolex received ODD from the European Medicines Agency (EMA) for the same indications. Epidiolex is also being studied in additional forms of epilepsy, including the EpiFOS exploratory study (NCT07233239) in focal-onset seizures. Important Safety Information & Indications CONTRAINDICATION: HYPERSENSITIVITY EPIDIOLEX (cannabidiol) oral solution is contraindicated in patients with a history of hypersensitivity to cannabidiol or any ingredients in the product. WARNINGS & PRECAUTIONS Hepatic Injury:EPIDIOLEX can cause dose-related transaminase elevations. Concomitant use of valproate and elevated transaminase levels at baseline increase this risk. Obtain transaminase and bilirubin levels prior to starting treatment, at 1, 3, and 6 months after initiation of treatment, and periodically thereafter, or as clinically indicated. Resolution of transaminase elevations occurred with discontinuation of EPIDIOLEX, reduction of EPIDIOLEX and/or concomitant valproate, or without dose reduction. For patients with elevated transaminase levels, consider dose reduction or discontinuation of EPIDIOLEX or concomitant medications known to affect the liver (e.g., valproate or clobazam). Dose adjustment and slower dose titration is recommended in patients with moderate or severe hepatic impairment. Consider not initiating EPIDIOLEX in patients with evidence of significant liver injury. There have been postmarketing reports of cholestatic or mixed patterns of liver injury. Elevated ammonia levels were reported in some patients with transaminase elevations; most taking concomitant valproate, clobazam, or both. Consider discontinuation or dose adjustment of valproate or clobazam if ammonia is elevated. Somnolence and Sedation:EPIDIOLEX can cause somnolence and sedation that generally occurs early in treatment and may diminish over time; these effects occur more commonly in patients using clobazam and may be potentiated by other CNS depressants. Suicidal Behavior and Ideation:Antiepileptic drugs (AEDs), including EPIDIOLEX, increase the risk of suicidal thoughts or behavior. Inform patients, caregivers, and families of the risk and advise them to monitor and report any signs of depression, suicidal thoughts or behavior, or unusual changes in mood or behavior. If these symptoms occur, consider if they are related to the AED or the underlying illness. Withdrawal of Antiepileptic Drugs:As with most AEDs, EPIDIOLEX should generally be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus. ADVERSE REACTIONS:The most common adverse reactions in patients receiving EPIDIOLEX (≥10% and greater than placebo) include transaminase elevations; somnolence; decreased appetite; diarrhea; pyrexia; vomiting; fatigue, malaise, and asthenia; rash; insomnia, sleep disorder and poor-quality sleep; and infections. Hematologic abnormalities were also observed. PREGNANCY:EPIDIOLEX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Encourage women who are taking EPIDIOLEX during pregnancy to enroll in the EPIDIOLEX Pregnancy Surveillance Program and the North American Antiepileptic Drug (NAAED) Pregnancy Registry. DRUG INTERACTIONS:Strong inducers of CYP3A4 and CYP2C19 may affect EPIDIOLEX exposure. EPIDIOLEX may affect exposure to CYP2C19 substrates (e.g., clobazam, diazepam, stiripentol), orally administered P-gp substrates, or other substrates (see full Prescribing Information). Consider dose reduction of orally administered everolimus, with appropriate therapeutic drug monitoring, when everolimus is combined with EPIDIOLEX. A lower starting dose of everolimus is recommended when added to EPIDIOLEX therapy. Concomitant use of EPIDIOLEX and valproate increases the incidence of liver enzyme elevations. Pneumonia was observed more frequently with concomitant use of EPIDIOLEX and clobazam. Dosage adjustment of EPIDIOLEX or other concomitant medications may be necessary. INDICATIONS:EPIDIOLEX (cannabidiol) oral solution is indicated for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), or tuberous sclerosis complex (TSC) in patients 1 year of age and older. Please read the EPIDIOLEX full Prescribing Information for additional important information here. About Jazz Pharmaceuticals Jazz Pharmaceuticals plc (Nasdaq: JAZZ) is a global biopharma company whose purpose is to innovate to transform the lives of patients and their families. We are dedicated to developing potentially life-changing medicines for people with serious diseases — often with limited or no therapeutic options. We have a diverse portfolio of marketed medicines, including leading therapies for sleep disorders and epilepsy, and a growing portfolio of cancer treatments. Our patient-focused and science-driven approach powers pioneering research and development advancements across our robust pipeline of innovative therapeutics in oncology and neuroscience. Jazz is headquartered in Dublin, Ireland with research and development laboratories, manufacturing facilities and employees in multiple countries committed to serving patients worldwide. Please visit www.jazzpharmaceuticals.com for more information. Contacts: Media: Kristin Bhavnani Head of Global Corporate Communications Jazz Pharmaceuticals plc CorporateAffairsMediaInfo@jazzpharma.com Ireland +353 1 637 2141 U.S. +1 215 867 4948 Investors: Jack Spinks Executive Director, Investor Relations Jazz Pharmaceuticals plc investorinfo@jazzpharma.com Ireland +353 1 634 3211U.S. +1 650 496 2717 References: ____________________ 1 TSC Alliance. What is TSC? https://www.tscalliance.org/understanding-tsc/what-is-tsc/. Accessed December 2025 . 2 National Institute of Neurological Disorders and Stroke. Tuberous Sclerosis Complex . https://www.ninds.nih.gov/health-information/disorders/tuberous-sclerosis-complex. Accessed December 2025 . 3 TSC Alliance. An introduction to tuberous sclerosis complex. https://www.tscalliance.org/wp-content/uploads/2023/12/An-introduction-to-TSC-2021.pdf. Accessed December 2025 . 4 Kingswood JC, d'Augères GB, Belousova E, et al. TuberOus SClerosis registry to increase disease Awareness (TOSCA) - baseline data on 2093 patients. 2017;12(1):2. 5 de Vries PJ, Belousova E, Benedik MP, et al. TSC-associated neuropsychiatric disorders (TAND): findings from the TOSCA natural history study. Orphanet J Rare Dis. 2018;13(1):157. 6 Tuberous Sclerosis Alliance. Diagnostic criteria. https://www.tscalliance.org/understanding-tsc/diagnosis-criteria/. Accessed December 2025 . 7 Jeong A, Wong M. Systemic disease manifestations associated with epilepsy in tuberous sclerosis complex. Epilepsia. 2016;57(9):1443-1449. 8 Chu-Shore CJ, Major P, Camposano S, Muzykewicz D, Thiele EA. The natural history of epilepsy in tuberous sclerosis complex. Epilepsia. 2010;51(7):1236-1241. 9 Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med. 2000;342(5):314-319. 10 French JA. Refractory epilepsy: clinical overview. Epilepsia. 2007;48 Suppl 1:3-7. 11 Epilepsy Foundation. Dravet Syndrome. https://www.epilepsy.com/what-is-epilepsy/syndromes/dravet-syndrome. Accessed December 2025 . 12 National Organization for Rare Disorders, Inc. Lennox-Gastaut Syndrome: Signs & Symptoms. https://rarediseases.org/rare-diseases/lennox-gastaut-syndrome/. Accessed December 2025 . View original content to download multimedia:https://www.prnewswire.com/news-releases/jazz-pharmaceuticals-to-present-extensive-new-data-and-real-world-evidence-highlighting-epidiolex-cannabidiol-outcomes-in-treatment-resistant-epilepsies-at-the-american-epilepsy-society-2025-annual-meeting-302633648.html SOURCE Jazz Pharmaceuticals plc