Background

The intravenous (IV) formulation of Rho-kinase (ROCK) inhibitor fasudil has been approved for the treatment of subarachnoid haemorrhage since 1995. Additionally, fasudil has shown promising preclinical results for various chronic diseases, including neurodegenerative diseases such as amyotrophic lateral sclerosis, Parkinson’s disease, and dementia, in which long-term intravenous (IV) administration might not be suitable.

Objective

The objective of this study was to assess the absolute bioavailability of oral, in comparison to IV, application of the approved formulation of fasudil (ERIL®) and to evaluate the safety and tolerability of the oral application of fasudil.

Methods

This was a phase I, single-center, open-label, randomized, two period cross-over clinical trial in healthy women and men. By applying a cross-over design, each subject served as their own control. Two treatments were investigated, separated by a wash out phase of at least 3 days. Oral fasudil was administered once on day 1 to assess pharmacokinetics and three times on day 2, at an interval of 8 ± 1 h, to assess safety and gastrointestinal tolerability. For pharmacometrics of IV fasudil, it was administered once on day 1. Plasma profiles of fasudil and its active metabolite hydroxyfasudil after oral or IV administration were measured by liquid chromatography electrospray tandem mass spectrometry. Tolerability was assessed as proportion of subjects without significant drug intolerance, and safety was assessed by the proportion of subjects without clinical or laboratory treatment-associated serious adverse events. Gastrointestinal safety was assessed by applying the gastrointestinal symptom rating scale (GSRS).

Results

Fourteen subjects aged 30–70 years were included in this trial. After oral administration, fasudil concentrations in blood were mostly very low [1.4 g/L; coefficient of variation (CV) 41.0%]. After IV application, the peak concentration was 100.6 µg/L (CV 74.2%); however, a high variance in peak concentrations were assessed for both treatments. The maximal concentrations of hydroxyfasudil in blood were similar after oral and IV treatment [111.6 µg/L (CV 24.1%) and 108.4 µg/L (CV 19.7%), respectively]. Exposure of hydroxyfasudil (assessed as AUC_0–tz) differed between both treatments, with 449 µg × h/L after IV treatment and 309 µg × h/L after oral treatment. Therefore, the absolute bioavailability of hydroxyfasudil after the oral treatment was approximately 69% of the IV treatment. No serious adverse events (SAEs) occurred during this trial, and good tolerability of oral fasudil (90 mg/day) was documented.

Conclusions

Oral fasudil was generally well tolerated in the studied population, and no safety concerns were identified. However, systemic bioavailability of oral hydroxyfasudil corresponded to 69%, and dose adjustments need to considered. The results presented here lay grounds for future trials of fasudil in chronic diseases, which require an oral long-term application. This trial was registered with EudraCT (no. 2019-001805-26).

中文翻译：

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SAFE-ROCK：口服 ROCK 抑制剂 Fasudil 的 I 期试验，以评估健康参与者的生物利用度、安全性和耐受性

背景

Rho 激酶 (ROCK) 抑制剂法舒地尔的静脉 (IV) 制剂自 1995 年以来已被批准用于治疗蛛网膜下腔出血。此外，法舒地尔在治疗各种慢性疾病方面显示出有希望的临床前结果，包括神经退行性疾病，如肌萎缩侧索硬化症、帕金森病疾病和痴呆症，长期静脉注射 (IV) 可能不适合。

客观的

本研究的目的是评估经批准的法舒地尔制剂 (ERIL®) 与静脉注射相比口服的绝对生物利用度，并评估口服法舒地尔的安全性和耐受性。

方法

这是一项针对健康女性和男性的 I 期、单中心、开放标签、随机、两期交叉临床试验。通过应用交叉设计，每个受试者都充当自己的对照。研究了两种治疗方法，间隔至少 3 天的清除阶段。口服法舒地尔第 1 天口服一次以评估药代动力学，第 2 天口服 3 次，间隔 8±1 小时，以评估安全性和胃肠道耐受性。对于静脉注射法舒地尔的药理学，第一天给药一次。通过液相色谱电喷雾串联质谱法测量口服或静脉注射后法舒地尔及其活性代谢物羟基法舒地尔的血浆分布。耐受性根据没有明显药物不耐受的受试者比例进行评估，安全性根据没有临床或实验室治疗相关严重不良事件的受试者比例进行评估。通过应用胃肠道症状评定量表（GSRS）评估胃肠道安全性。

结果

本试验纳入了 14 名年龄在 30-70 岁之间的受试者。口服给药后，法舒地尔的血药浓度大多非常低[1.4 g/L；变异系数（CV）41.0%]。静脉注射后，峰值浓度为100.6 µg/L（CV 74.2%）；然而，两种处理的峰值浓度存在很大差异。口服和静脉注射治疗后，血液中羟基法舒地尔的最大浓度相似[分别为 111.6 µg/L (CV 24.1%) 和 108.4 µg/L (CV 19.7%)]。两种治疗之间羟基法舒地尔的暴露量（评估为 AUC _0-tz）不同，静脉注射治疗后为 449 µg × h/L，口服治疗后为 309 µg × h/L。因此，口服治疗后羟基法舒地尔的绝对生物利用度约为静脉注射治疗的69%。该试验期间没有发生严重不良事件 (SAE)，并且记录了口服法舒地尔（90 毫克/天）的良好耐受性。

结论

口服法舒地尔在研究人群中普遍耐受性良好，并且没有发现安全问题。然而，口服羟基法舒地尔的全身生物利用度为 69%，需要考虑剂量调整。这里提出的结果为未来法舒地尔治疗慢性疾病的试验奠定了基础，这些慢性疾病需要长期口服应用。该试验已在 EudraCT 注册（编号 2019-001805-26）。