SAFE-ROCK: A Phase I Trial of an Oral Application of the ROCK Inhibitor Fasudil to Assess Bioavailability, Safety, and Tolerability in Healthy Participants.

IF 7.4 2区 医学 Q1 CLINICAL NEUROLOGY CNS drugs Pub Date : 2024-04-01 Epub Date: 2024-02-28 DOI:10.1007/s40263-024-01070-7
Andreas W Wolff, Jörg Peine, Josef Höfler, Gabriela Zurek, Claus Hemker, Paul Lingor
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Abstract

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 AUC0-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).

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SAFE-ROCK:口服 ROCK 抑制剂 Fasudil 的 I 期试验,评估健康参与者的生物利用度、安全性和耐受性。
背景:自 1995 年以来,Rho-激酶(ROCK)抑制剂法舒地尔的静脉注射制剂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(包括神经退行性疾病,如肌萎缩性脊髓侧索硬化症、帕金森病和痴呆症)的临床前研究中也显示出良好的效果,因为在这些疾病中可能不适合长期静脉注射:本研究旨在评估口服法舒地尔(ERIL®)批准制剂的绝对生物利用度(与静脉注射相比),并评估口服法舒地尔的安全性和耐受性:这是一项在健康女性和男性中进行的一期、单中心、开放标签、随机、两期交叉临床试验。通过采用交叉设计,每个受试者都作为自己的对照组。试验采用两种治疗方法,中间有至少 3 天的冲淡期。第1天口服法舒地尔一次,以评估药代动力学;第2天口服三次,每次间隔8±1小时,以评估安全性和胃肠道耐受性。静脉注射法舒地尔的药代动力学评估在第1天进行一次。通过液相色谱电喷雾串联质谱法测定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概况。耐受性以无明显药物不耐受的受试者比例进行评估,安全性以无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。胃肠道安全性通过胃肠道症状评分量表(GSRS)进行评估:14名年龄在30-70岁之间的受试者参加了此次试验。口服后,法舒地尔在血液中的浓度大多很低[1.4克/升;变异系数(CV)41.0%]。静脉注射后,峰值浓度为 100.6 µg/L(变异系数为 74.2%);然而,两种治疗方法的峰值浓度差异都很大。口服和静脉注射后,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%)]。两种治疗方法的羟基法舒地暴露量(以AUC0-tz评估)不同,静脉注射治疗后为449微克×小时/升,口服治疗后为309微克×小时/升。因此,口服治疗后羟氟地尔的绝对生物利用度约为静脉注射治疗的 69%。试验期间未发生严重不良事件(SAE),口服法舒地尔(90 毫克/天)的耐受性良好:结论:研究对象对口服法舒地尔的耐受性普遍良好,未发现任何安全问题。然而,口服羟基法舒地尔的全身生物利用度为69%,因此需要考虑调整剂量。本文介绍的结果为今后法舒地尔在需要长期口服的慢性疾病中的试验奠定了基础。该试验已在EudraCT注册(编号:2019-001805-26)。
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来源期刊
CNS drugs
CNS drugs 医学-精神病学
CiteScore
12.00
自引率
3.30%
发文量
82
审稿时长
6-12 weeks
期刊介绍: CNS Drugs promotes rational pharmacotherapy within the disciplines of clinical psychiatry and neurology. The Journal includes: - Overviews of contentious or emerging issues. - Comprehensive narrative reviews that provide an authoritative source of information on pharmacological approaches to managing neurological and psychiatric illnesses. - Systematic reviews that collate empirical evidence to answer a specific research question, using explicit, systematic methods as outlined by the PRISMA statement. - Adis Drug Reviews of the properties and place in therapy of both newer and established drugs in neurology and psychiatry. - Original research articles reporting the results of well-designed studies with a strong link to clinical practice, such as clinical pharmacodynamic and pharmacokinetic studies, clinical trials, meta-analyses, outcomes research, and pharmacoeconomic and pharmacoepidemiological studies. Additional digital features (including animated abstracts, video abstracts, slide decks, audio slides, instructional videos, infographics, podcasts and animations) can be published with articles; these are designed to increase the visibility, readership and educational value of the journal’s content. In addition, articles published in CNS Drugs may be accompanied by plain language summaries to assist readers who have some knowledge of, but not in-depth expertise in, the area to understand important medical advances.
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