Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Tel Aviv University, Haharuv 18, PO Box 184, 36576, Timrat, Israel.
CNS Drugs. 2018 May;32(5):443-454. doi: 10.1007/s40263-018-0512-x.
Subcutaneous apomorphine is used for the treatment of Parkinson's disease (PD); however, infusion site reactions are a common adverse event (AE), which can lead to treatment discontinuation. Apomorphine formulations that are more tolerable and convenient for use are needed.
Our aim was to compare the toxicity and bioavailability of ND0701, a new concentrated formulation of apomorphine free base, with one of the commercially available apomorphine HCl formulations (APO-go, Britannia Pharmaceuticals Ltd).
(1) Preclinical study: 16 minipigs were randomly assigned to placebo, APO-go, and ND0701 groups, and treated for 28 days. Pharmacokinetic, clinical, and pathological assessments were performed. (2) Phase I study: 18 healthy volunteers participated in an open-label, two-sequence, randomized, three single-dose, partial crossover study to compare the pharmacokinetics, safety, and tolerability of ND0701 with APO-go (1%).
(1) Preclinical study: No systemic toxicity was observed in apomorphine-treated minipigs, but local skin reactions were observed at the infusion sites. These effects were less frequent and less severe and recovery was more rapid for ND0701 compared with APO-go. (2) Phase I study: Both formulations were safe and well tolerated under the conditions of the study and no severe or serious treatment-emergent AEs were reported. Infusion site nodules were reported more frequently, with higher severity, and recovered slower at APO-go-treated sites compared with ND0701-treated sites. Bioavailability of apomorphine was comparable between the two formulations.
Based on these pilot studies, ND0701 appears to be superior to APO-go in terms of tolerability and safety, while maintaining comparable bioavailability with APO-go, and shows promise as a future treatment for PD.
皮下给予阿朴吗啡可用于治疗帕金森病（PD）；然而，输注部位反应是一种常见的不良反应（AE），可能导致治疗中断。需要使用更耐受和方便使用的阿朴吗啡制剂。
我们旨在比较新型游离碱阿朴吗啡浓缩制剂 ND0701 与一种市售阿朴吗啡盐酸盐制剂（APO-go，Britannia Pharmaceuticals Ltd）的毒性和生物利用度。
（1）临床前研究：16 头小型猪随机分为安慰剂、APO-go 和 ND0701 组，治疗 28 天。进行药代动力学、临床和病理学评估。（2）I 期研究：18 名健康志愿者参加了一项开放标签、两序列、随机、三单剂量、部分交叉研究，以比较 ND0701 与 APO-go（1%）的药代动力学、安全性和耐受性。
（1）临床前研究：在接受阿朴吗啡治疗的小型猪中未观察到全身毒性，但在输注部位观察到局部皮肤反应。与 APO-go 相比，ND0701 引起的这些反应频率较低、程度较轻，且恢复较快。（2）I 期研究：在研究条件下，两种制剂均安全且耐受良好，未报告严重或严重的治疗后出现的不良事件。与 ND0701 治疗部位相比，APO-go 治疗部位报告的输注部位结节更频繁、更严重且恢复更慢。两种制剂的阿朴吗啡生物利用度相当。
基于这些初步研究，与 APO-go 相比，ND0701 在耐受性和安全性方面似乎更具优势，同时保持与 APO-go 相当的生物利用度，有望成为 PD 的未来治疗方法。
