Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA, United States of America.
Tox Path Specialists, LLC (a StageBio Company), Frederick, MD, United States of America.
PLoS One. 2023 Aug 22;18(8):e0277718. doi: 10.1371/journal.pone.0277718. eCollection 2023.
Riluzole is the only treatment known to improve survival in patients with Amyotrophic Lateral Sclerosis (ALS). However, oral riluzole efficacy is modest at best, further it is known to have large inter-individual variability of serum concentration and clearance, is formulated as an oral drug in a patient population plagued with dysphagia, and has known systemic side-effects like asthenia (limiting patient compliance) and elevated liver enzymes. In this context, we postulated that continuous intrathecal (IT) infusion of low doses of riluzole could provide consistent elevations of the drug spinal cord (SC) concentrations at or above those achieved with oral dosing, without increasing the risk for adverse events associated with systemic drug exposure or off-target side effects in the brain. We developed a formulation of riluzole for IT delivery and conducted our studies in purpose-bred hound dogs. Our non-GLP studies revealed that IT infusion alone was able to increase SC concentrations above those provided by oral administration, without increasing plasma concentrations. We then conducted two GLP studies that combined IT infusion with oral administration at human equivalent dose, to evaluate SC and brain concentrations of riluzole along with assessments of safety and tolerability. In the 6-week study, the highest IT dose (0.2 mg/hr) was well tolerated by the animals and increased SC concentrations above those achieved with oral riluzole alone, without increasing brain concentrations. In the 6-month study, the highest dose tested (0.4 mg/hr) was not tolerated and yielded SC significantly above those achieved in all previous studies. Our data show the feasibility and safety profile of continuous IT riluzole delivery to the spinal cord, without concurrent elevated liver enzymes, and minimal brain concentrations creating another potential therapeutic route of delivery to be used in isolation or in combination with other therapeutics."
利鲁唑是唯一已知可改善肌萎缩侧索硬化症（ALS）患者生存的治疗方法。然而，口服利鲁唑的疗效充其量只是适度的，此外，它已知具有个体间血清浓度和清除率的巨大差异，在因吞咽困难而饱受困扰的患者人群中被制成口服药物，并且具有已知的全身性副作用，如乏力（限制患者依从性）和肝酶升高。在这种情况下，我们假设持续鞘内（IT）输注低剂量的利鲁唑可以在不增加与全身药物暴露相关的不良反应或大脑中脱靶副作用的风险的情况下，提供药物脊髓（SC）浓度的持续升高，达到或超过口服剂量所达到的水平。我们开发了一种利鲁唑的 IT 递药制剂，并在专门饲养的猎犬中进行了研究。我们的非 GLP 研究表明，单独的 IT 输注就能增加 SC 浓度，超过口服给药提供的浓度，而不会增加血浆浓度。然后，我们进行了两项 GLP 研究，将 IT 输注与人类等效剂量的口服给药相结合，以评估利鲁唑的 SC 和脑浓度，以及安全性和耐受性评估。在 6 周的研究中，最高 IT 剂量（0.2mg/hr）被动物很好地耐受，增加了 SC 浓度，超过了单独口服利鲁唑的浓度，而没有增加脑浓度。在 6 个月的研究中，测试的最高剂量（0.4mg/hr）不能耐受，并且 SC 浓度显著高于所有先前研究中达到的浓度。我们的数据表明，持续 IT 利鲁唑递送至脊髓的可行性和安全性，而不会同时出现升高的肝酶和最小的脑浓度，为单独或与其他治疗方法联合使用提供了另一种潜在的治疗途径。
