Algorithm for managing infusion site adverse events caused by subcutaneous foslevodopa/foscarbidopa and other device-aided therapies for advanced Parkinson's disease

Article

作者: Mendes-Bastos, Pedro ; Simoes, Rita Moiron

A review.Advanced Parkinson′s disease (PD) presents significant management challenges, particularly due to motor fluctuations, dyskinesias, and impaired oral medication efficacy resulting from neuronal degeneration and disrupted gastrointestinal function.Traditional oral dopaminergic treatments are often ineffective at this stage, prompting the development of advanced device-mediated therapies such as foslevodopa/foscarbidopa (pLD/pCD), a prodrug for s.c. (s.c.) levodopa/carbidopa infusion.This formulation offers continuous, stable dopamine exposure and has demonstrated benefits in improving motor control, quality of life, and reducing off time.However, a notable safety concern associated with pLD/pCD therapy is the high incidence of infusion site adverse events (ISAE), particularly skin reactions such as pain, erythema, irritation, and nodules, which can lead to treatment discontinuation in a significant proportion of patients.This paper provides an in-depth review of the dermatol. ISAE associated with s.c. infusion therapies, including pLD/pCD, and offers practical guidance for healthcare providers (HCPs) in diagnosing and managing these reactions.A clin. management algorithm is proposed, which includes strategies for addressing nociceptive pain, erythema, infections, and eczema/dermatitis.Emphasis is placed on recognizing early symptoms, differentiating between various types of reactions, and implementing preventive measures to minimize patient discomfort and prevent escalation of adverse events.The importance of frequent monitoring, repositioning of infusion sites, and appropriate treatment with topical antibiotics or corticosteroids is underscored.Given the growing use of s.c. infusion therapies in PD, this algorithm aims to empower HCPs with the knowledge to manage ISAE effectively, ensuring optimal therapeutic outcomes and enhancing patient quality of life.The study also highlights the need for a multidisciplinary approach involving neurologists, nurses, and dermatologists to address complex cases and suggests that real-world studies are essential to refine current practices and improve long-term patient care.

2024-04-01·Pharmacology research & perspectives

Metabolite profiling of foslevodopa/foscarbidopa in plasma of healthy human participants by LC‐HRMS indicates no major differences compared to administration of levodopa/carbidopa intestinal gel

Article

作者: Burton, Richard ; Smith, Richard L ; Rosebraugh, Matthew ; Neenan, Melina ; Marsh, Kennan ; Savaryn, John P ; Wagner, David

Abstract:

Analysis was conducted to compare levodopa/carbidopa pharmacokinetics and drug‐related material in plasma of healthy participants after receiving a continuous infusion of Levodopa/Carbidopa Intestinal Gel (LCIG) to a continuous subcutaneous infusion of foslevodopa/foscarbidopa. Study samples were from a randomized, open‐label, 2‐period crossover study in 20 healthy participants. Participants received either 24‐h foslevodopa/foscarbidopa SC infusion to the abdomen or LCIG delivered for 24 h to the jejunum through a nasogastric tube with jejunal extension. Serial blood samples were collected for PK. Comparability of the LD PK parameters between the two treatment regimens was determined. Selected plasma samples were pooled per treatment group and per time point for metabolite profiling. LC–MSn was performed using high‐resolution mass spectrometry to identify drug‐related material across the dosing regimens and time points. The LD PK parameter central values and 90% confidence intervals following the foslevodopa/foscarbidopa subcutaneous infusion were between 0.8 and 1.25 relative to the LCIG infusion. With LCIG administration, LD, CD, 3‐OMD, DHPA, DOPAC, and vanillacetic acid were identified in plasma at early and late time points (0.75 and 24 h); the metabolic profile after administration of foslevodopa/foscarbidopa demonstrated the same drug‐related compounds with the exception of the administered foslevodopa. 3‐OMD and vanillacetic acid levels increased over time in both treatment regimens. Relative quantification of LC–MS peak areas showed no major differences in the metabolite profiles. These results indicate that neither the addition of monophosphate prodrug moieties nor SC administration affects the circulating metabolite profile of foslevodopa/foscarbidopa compared to LCIG.

2023-04-01·Clinical pharmacology in drug development

Comparability of Foslevodopa/Foscarbidopa Pharmacokinetics in Healthy Asian and White Participants

Article

作者: Rosebraugh, Matthew ; Neenan, Melina ; Facheris, Maurizio

Abstract:

This phase 1 study assessed the safety, tolerability, and pharmacokinetics of a single 24‐hour continuous subcutaneous dose of foslevodopa/foscarbidopa in healthy adult Japanese (N = 24), Han Chinese (N = 8), and White (N = 24) participants. Three doses of foslevodopa/foscarbidopa were evaluated in healthy participants for this study: 480/24, 960/48, and 1440/72 mg/day. Serial blood samples for measurement of levodopa, carbidopa, foslevodopa, foscarbidopa, and 3‐O‐methyldopa concentrations were collected for 48 hours after foslevodopa/foscarbidopa administration. Safety and tolerability were assessed throughout the study. Point estimates for ratios of central values indicated that the exposure difference between Japanese and White participants was <10%. The maximum concentration and area under the plasma concentration–time curve for both LD and CD following foslevodopa/foscarbidopa continuous subcutaneous infusion were comparable between Han Chinese and White participants. Point estimates for ratios of central values indicated that the exposure difference between Han Chinese and White participants was <14%. The regimens tested were generally well tolerated, and no new safety issues were identified in this study. There were no clinically meaningful differences in LD and CD exposures or pharmacokinetics following administration of foslevodopa/foscarbidopa among White, Japanese, and Han Chinese participants.

项与 Foslevodopa 相关的新闻（医药）

2024-10-21

·药明康德

首款！FDA批准艾伯维帕金森病疗法

艾伯维（AbbVie）宣布，美国FDA已批准Vyalev（foscarbidopa和foslevodopa）上市，用于治疗晚期帕金森病（PD）成人患者的运动能力波动。新闻稿指出，这是FDA批准的首款基于左旋多巴的皮下24小时持续输注疗法。这一批准主要基于一项为期12周的关键性3期临床试验，该研究评估了Vyalev在晚期PD成人患者中持续皮下输注的疗效，并与口服即释型卡比多巴/左旋多巴进行了对比。此外，还有一项为期52周的开放标签研究，评估了Vyalev的长期安全性和有效性。关键性临床试验结果显示，接受Vyalev治疗的患者在运动能力波动改善方面表现出更佳效果，与口服药物相比，其运动症状控制较佳的时间增加，运动障碍症状回归的时间减少。在第12周时，Vyalev组运动症状控制较佳的时间增加2.72小时，活性对照组这一数值为0.97小时（p=0.0083）。这项研究的详细数据已经在The Lancet Neurology杂志上发表。 Vyalev的大部分不良反应（ARs）为轻度至中度。最常见的不良反应（发生率≥10%且高于活性对照组）为注射部位反应、幻觉和运动障碍（dyskinesia）。全球有超过1000万人正在与帕金森病作斗争。这是一种逐渐进展的慢性神经系统疾病，以震颤、肌肉僵硬、动作缓慢和平衡困难为特征。帕金森病的运动症状通常在脑内多巴胺产生细胞丧失约60-80%时开始出现，且症状会随着时间推移逐步恶化。上世纪70年代以来，患者主要的治疗方法为左旋多巴。然而随着时间的推移，左旋多巴可能导致不自主、不受控制的运动，称为运动障碍。在晚期患者中，口服左旋多巴面对多种挑战，例如患者的胃肠道功能下降导致药物无法及时进入体内，而且口服药物不能将患者体内的药物浓度维持在一个稳定水平，也导致患者运动障碍的加剧。 Vyalev是左旋多巴和卡比多巴的前体药物。它们具有很高的水溶性，可以通过一个连接到皮下的泵持续皮下输注给药，从而稳定维持药物在体内的浓度。参考资料： [1] U.S. FDA Approves VYALEV™ (foscarbidopa and foslevodopa) for Adults Living with Advanced Parkinson's Disease. Retrieved October 17, 2024, from https://www.prnewswire.com/news-releases/us-fda-approves-vyalev-foscarbidopa-and-foslevodopa-for-adults-living-with-advanced-parkinsons-disease-302278666.html 内容来源于网络，如有侵权，请联系删除。

上市批准临床结果

2022-05-27

·生物谷

晚期帕金森病(PD)新药！艾伯维ABBV-951在美国申请上市：疗效显著优于口服左旋多巴/卡比多巴!

ABBV-951旨在提供同类首个24小时持续皮下递送CD/LD的治疗方法。与口服CD/LD相比，可改善晚期PD患者的运动症状波动。艾伯维（AbbVie）近日宣布，已向美国食品和药物管理局（FDA）ABBV-951（foscarbidopa/foslevodopa）的新药申请（NDA），该药是一种左旋多巴前药（foslevodopa）和卡比多巴前药（foscarbidopa）的溶液，通过持续皮下给药，用于治疗晚期帕金森病（PD）患者的运动症状波动（motor fluctuations，MF）。如果获得批准，ABBV-951将为晚期PD患者提供第一种卡比多巴/左旋多巴前药的持续皮下递送疗法。来自3期临床试验的数据显示，与口服速释卡比多巴/左旋多巴（levodopa/carbidopa，CD/LD）相比，接受ABBV-951治疗的患者，无令人烦恼的运动障碍（不自主运动）的“ON”时间在统计学上显著增加。帕金森病（PD）是一种进行性的慢性神经系统疾病，由产生多巴胺的脑细胞丧失所致，主要表现为震颤、肌肉僵硬、运动缓慢和平衡困难。在PD患者中，患者与其医疗保健提供者有着相同的目标：延长“ON”时间，即症状得到良好控制且无运动障碍或不自主运动的时间。 ABBV-951旨在提供同类首个24小时持续皮下递送CD/LD的治疗方法。与口服CD/LD相比，可改善晚期PD患者的运动症状波动。 ABBV-951 NDA主要基于头对头优势比较3期M15-736研究（NCT04380142）的数据。这是一项随机、双盲、双模拟、阳性药物对照研究，在约130例晚期PD患者中开展，这些患者的运动症状已无法通过目前的药物得到充分控制。研究中，患者被随机分为2组，一组接受连续24小时/天皮下输注ABBV-951，另一组接受口服左旋多巴/卡比多巴（LD/CD），治疗12周。研究的主要终点是：根据帕金森病日记（PD Diary）评估的运动状态，治疗12周后，无令人烦恼的运动障碍（不自主运动）的“ON”时间（小时）相对基线的增加。该研究达到了主要终点：在减少晚期PD患者运动波动方面，ABBV-951在统计学上优于口服LD/CD。具体数据为：治疗12周，ABBV-951治疗组“ON”时间增加2.72小时，而口服LD/CD治疗组增加0.97小时（p=0.0083）。ABBV-951治疗组早在第一周就观察到“ON”时间的改善，并持续至第12周。此外，还观察到平均每日标准化“OFF”时间从基线有相似模式的改善。与口服LD/CD治疗组相比，ABBV-951治疗组早在第一周就观察到“OFF”时间的改善，并持续至第12周。具体数据为：治疗12周后，ABBV-951治疗组“OFF”时间减少了2.75小时，而口服LD/CD治疗组减少0.96小时（p=0.0054）。该研究中，ABBV-951组报告的大多数不良事件（AE）为非严重和轻中度。严重不良事件的发生率，在ABBV-951组和口服LD/CD组分别为8%和6%。口服LD/CD组有一名患者因治疗期不良事件（TEAE）导致死亡，而ABBV-951组没有发生死亡。ABBV-951组报告的最常见不良事件（≥10%）为输液部位不良反应（红斑、疼痛、蜂窝织炎、水肿）、运动障碍。（生物谷Bioon.com）原文出处：AbbVie Submits New Drug Application to U.S. FDA for Investigational ABBV-951 (Foscarbidopa/Foslevodopa) for the Treatment of Advanced Parkinson's Disease