de Jong Lara, Luinstra Marianne, Aalbers Angela Francesca, Wijma-Vos Alide Johanna, D'Angremont Emile, van der Meulen Anne Aline Elisabeth, Rutgers Antonie Wijnand Frederik, Steenhuis Luc, Hagedoorn Paul, van Laar Teus, Frijlink Hendrik Willem
Department of Clinical Pharmacy, Martini Hospital Groningen, Van Swietenplein 1, Groningen 9728 NT, The Netherlands.
Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, The Netherlands.
Ther Adv Neurol Disord. 2024 Oct 25;17:17562864241289207. doi: 10.1177/17562864241289207. eCollection 2024.
Limited treatment options with a rapid onset of action are available to treat off episodes in Parkinson's disease (PD) patients. Therefore, the development of rapid onset formulations, for instance with levodopa, is warranted, which was the reason to investigate an inhalable formulation of levodopa.
The primary objective was to determine the duration until maximum effect is reached of inhaled levodopa on the improvement of motor function of PD patients. The secondary objective was to compare the time until maximal effect and the maximal effect of inhaled levodopa versus oral levodopa.
Open-label randomized two-way one-period crossover trial.
Nine PD patients in the 'off state' received one dose of inhaled levodopa (90 mg) from Cyclops® and one dose of levodopa orodispersible tablet (100 mg) on two consecutive days in a randomized order. A timed tapping test, Timed Up and Go test (TUG test) and Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) III score were performed pre-dose and on set time points up to 90 min post-dose as measure for motor function. In addition, blood samples were taken for a pharmacokinetic evaluation ( , and area under the concentration time curve (AUC) 0-3 h).
The maximal effect of inhaled levodopa was reached at 30 min (tapping test), at 75 min (TUG test) and at 60 min (UPDRS III). The positive effect on the UPDRS was statistically significant within 20 min after inhalation. After oral administration, and AUC 0-3 h were found to be significant higher ( = 0.028 and = 0.028, respectively) than after pulmonary administration. was achieved significantly ( = 0.028) faster after inhalation. The motor function examinations showed a similar maximum clinical improvement after pulmonary and oral administration and although not significant, inhaled levodopa results in a shorter median duration to maximum clinical effect for the TUG and timed finger-tapping test compared with oral administration (TUG: inhalation 55.0 and oral 67.5 min, timed finger-tapping test: inhalation 35.0 and oral 57.5 min). After the levodopa inhalation, there were no adverse events observed and no significant differences found in long-function parameters.
Inhaled levodopa from Cyclops shows promising data as a rescue therapy for PD patients with off episodes, not responsive to the current oral therapies.
The study protocol was approved by the local ethics board 'Regionale toetsingscommissie patiëntgebonden onderzoek' (RTPO) in Leeuwarden, The Netherlands (approval number RTPO1019). The study was registered in in the Dutch trial register (LTR) with identification number NL6876. From 5 March 2024 on, the research data on onderzoekmetmensen.nl are known as 'Overview of Medical Research in the Netherlands' (OMON). This means the use of the name LTR has thus been dropped. Now, it is registered in the OMON with the same identification number (NL6876, Effectiveness of inhaled levodopa in PD | Research with human participants (onderzoekmetmensen.nl)). All patients provided written informed consent.
帕金森病（PD）患者在“关”期发作时，起效迅速的治疗选择有限。因此，开发起效迅速的制剂，例如左旋多巴制剂，是很有必要的，这也是研究左旋多巴吸入制剂的原因。
主要目的是确定吸入左旋多巴改善PD患者运动功能达到最大效应的持续时间。次要目的是比较吸入左旋多巴与口服左旋多巴达到最大效应的时间以及最大效应。
开放标签随机双向单周期交叉试验。
9名处于“关”状态的PD患者连续两天随机接受一剂来自Cyclops®的吸入左旋多巴（90毫克）和一剂左旋多巴口腔崩解片（100毫克）。在给药前以及给药后直至90分钟的设定时间点进行定时敲击试验、计时起立行走试验（TUG试验）和运动障碍协会统一帕金森病评定量表（MDS-UPDRS）III评分，作为运动功能的测量指标。此外，采集血样进行药代动力学评估（ 、 以及浓度-时间曲线下面积（AUC）0-3小时）。
吸入左旋多巴在30分钟时（敲击试验）、75分钟时（TUG试验）和60分钟时（UPDRS III）达到最大效应。吸入后20分钟内，对UPDRS的积极影响具有统计学意义。口服给药后， 和AUC 0-3小时显著高于肺部给药（分别为 =0.028和 =0.028）。吸入后达到 显著更快（ =0.028）。运动功能检查显示肺部给药和口服给药后最大临床改善相似，尽管不显著，但与口服给药相比，吸入左旋多巴在TUG试验和定时手指敲击试验中达到最大临床效应的中位持续时间更短（TUG试验：吸入55.0分钟，口服67.5分钟；定时手指敲击试验：吸入35.0分钟，口服57.5分钟）。吸入左旋多巴后，未观察到不良事件，在长期功能参数方面未发现显著差异。
来自Cyclops的吸入左旋多巴作为对当前口服治疗无反应的PD“关”期发作患者的急救疗法显示出有前景的数据。
该研究方案已获得荷兰吕伐登当地伦理委员会“地区患者相关研究审查委员会”（RTPO）的批准（批准号RTPO1019）。该研究已在荷兰试验注册中心（LTR）注册，识别号为NL6876。从2024年3月5日起，onderzoekmetmensen.nl上的研究数据称为“荷兰医学研究概述”（OMON）。这意味着LTR这个名称已不再使用。现在，它以相同的识别号（NL6876，吸入左旋多巴在帕金森病中的有效性 | 人体参与者研究（onderzoekmetmensen.nl））在OMON中注册。所有患者均提供了书面知情同意书。
