缺血性中风已成为中国死亡和成人残疾的主要原因。溴唑戊钠(BZP),缺血性中风的创新药物,由浙江奥森药业有限公司精心研发,有限公司(中国)。这项首次针对人类的研究探讨了BZP的安全性,耐受性,中国健康志愿者的药代动力学(PK)特征。结果证实BZP是安全的,耐受性良好,并在单次和多次上行静脉输注后显示可预测的PK特征。这些结果支持BZP对缺血性卒中患者的进一步发展潜力。
背景:溴唑戊基钠(BZP),一种治疗缺血性中风的新型药物,在临床前药理学研究中显示出有希望的结果,促使人类首次调查的开始。
目的:本研究旨在评估安全性,耐受性,BZP在中国健康志愿者中的药代动力学(PK)特征。
方法:本研究由两部分组成。第一部分是一个单一的中心,随机化,单盲,安慰剂对照,采用六个BZP剂量组(SAD:25、50、100、200、300和400mg)的单次递增研究。第二部分是单中心,随机化,单盲,安慰剂对照,使用三个BZP剂量组(MAD:50、100和200mg)的多剂量和剂量升高研究。剂量在第1天和第7天每天施用一次,在第2-6天每天施用两次。BZP及其生物活性代谢产物的PK特性,BNBP,被评估。还进行了安全性和耐受性评价。
结果:在SAD研究中,BZP在给药结束时达到峰值血浆浓度(Tmax),Tmax的中值范围为1至1.03小时,而BNBP在1.25至1.38小时之间达到Tmax。终末半衰期(T1/2)对于BZP约为8小时,对于BNBP约为15小时。在MAD研究中,BZP的稳态血浆浓度在第5天达到。给药7天后,BZP和BNBP的积累都很少。在两个研究部分中,从0到最后可测量浓度(AUC0-t)和最大血浆药物浓度(Cmax)的时间的血浆浓度-时间曲线下面积显示出BZP的剂量成比例增加,而BNBP的剂量成比例增加。单剂量和多剂量的BZP表现出良好的安全性,并且耐受性良好。
结论:BZP显示安全性,良好的耐受性和可预测的PK特性在单次和多次上行静脉给药后。这些发现为缺血性脑卒中患者BZP的进一步临床开发提供了依据。
BACKGROUND: Brozopentyl Sodium (BZP), a novel agent for ischemic stroke, has shown promising results in preclinical pharmacological studies, prompting the initiation of the first-in-human investigation.
OBJECTIVE: This study aimed to assess the safety, tolerability, and pharmacokinetic (PK) characteristics of BZP in Chinese healthy volunteers.
METHODS: The study consisted of two parts. Part I was a single-center, randomized, single-blinded, placebo-controlled, single-ascending study with six BZP dose cohorts (SAD: 25, 50, 100, 200, 300, and 400 mg). Part II was a single-center, randomized, single-blinded, placebo-controlled, multi-dose- and dose-elevated study with three BZP dose cohorts (MAD: 50, 100, and 200 mg). Doses were administered once daily on days 1 and 7 and twice daily on days 2-6. The PK properties of BZP and its bioactive metabolites, BNBP, were assessed. Safety and tolerability evaluations were also conducted.
RESULTS: In the SAD study, BZP reached peak plasma concentrations (Tmax) at the end of administration, with median Tmax values ranging from 1 to 1.03 h, while BNBP reached Tmax between 1.25 to 1.38 h. The terminal half-lives (T1/2) were approximately 8 h for BZP and 15 h for BNBP. In the MAD study, steady-state plasma concentrations of BZP were reached by day 5. There was minimal accumulation of both BZP and BNBP after 7 days of administration. The area under the plasma concentration-time curve from 0 to time of the last measurable concentration (AUC0-t) and maximum plasma drug concentration (Cmax) showed dose-proportional increases for BZP but not for BNBP in both study parts. Single and multiple doses of BZP demonstrated a good safety profile and were well-tolerated.
CONCLUSIONS: BZP displayed safety, good tolerability and predictable PK characteristics following both single and multiple ascending intravenous administrations. These findings provide a basis for further clinical development of BZP for ischemic stroke patients.