Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, IL.
Discovery Centralized Medicinal Chemistry, AbbVie Inc., North Chicago, IL.
Ann Neurol. 2021 Jul;90(1):52-61. doi: 10.1002/ana.26073. Epub 2021 May 4.
The aim was to demonstrate that continuous s.c. infusion of a soluble levodopa (LD)/carbidopa (CD) phosphate prodrug combination effectively delivers stable LD exposure via a minimally invasive and convenient mode and has the potential to treat Parkinson's disease (PD) patients who are not well controlled on oral medication.
Foslevodopa and foscarbidopa were prepared and the equilibrium solubility and chemical stability examined in aqueous media with different values of pH. Solutions of foslevodopa/foscarbidopa (ratios ranging from 4:1 to 20:1) were prepared by dissolving pH-adjusted lyophilized materials in water and infused s.c. in healthy volunteers for ≤72 hours. Frequent blood samples were collected to measure LD and CD exposure, and safety was monitored throughout the study.
Foslevodopa/foscarbidopa (ABBV-951) demonstrates high water solubility and excellent chemical stability near physiological pH, enabling continuous s.c. infusion therapy. After s.c. infusion, a stable LD pharmacokinetic (PK) profile was maintained for ≤72 hours, and the infusion was well tolerated.
Preparation of foslevodopa and foscarbidopa enables preclinical and clinical PK, safety, and tolerability studies in support of their advancement for the treatment of PD. In phase 1 clinical trials, foslevodopa/foscarbidopa demonstrates consistent and stable LD plasma exposure, supporting further studies of this treatment as a potentially transformational option for those suffering from PD. ANN NEUROL 2021;90:52-61.
旨在证明持续皮下输注可溶解左旋多巴（LD）/卡比多巴（CD）磷酸前药组合，通过微创、便捷的方式提供稳定的 LD 暴露，并有潜力治疗口服药物治疗效果不佳的帕金森病（PD）患者。
制备 Foslevodopa 和 Foscarbidopa，并在不同 pH 值的水介质中检查其平衡溶解度和化学稳定性。通过将 pH 调整的冻干材料溶解在水中制备 Foslevodopa/Foscarbidopa（比值范围为 4:1 至 20:1）溶液，并在健康志愿者中皮下输注≤72 小时。频繁采集血样以测量 LD 和 CD 暴露，并在整个研究过程中监测安全性。
Foslevodopa/Foscarbidopa（ABBV-951）在接近生理 pH 值的条件下具有高水溶性和优异的化学稳定性，可实现持续皮下输注治疗。皮下输注后，≤72 小时内可维持稳定的 LD 药代动力学（PK）曲线，且输注耐受性良好。
Foslevodopa 和 Foscarbidopa 的制备使临床前和临床 PK、安全性和耐受性研究成为可能，支持将其推进用于治疗 PD。在 1 期临床试验中，Foslevodopa/Foscarbidopa 显示出一致且稳定的 LD 血浆暴露，支持进一步研究这种治疗方法作为 PD 患者潜在的变革性选择。ANN NEUROL 2021；90:52-61。
