Admiraal M M, Velseboer D C, Tjabbes H, Vis P, Peeters-Scholte C, Horn J
Department of Clinical Neurophysiology, Amsterdam UMC, Amsterdam, Netherlands.
Amsterdam Neurosciences, Amsterdam, Netherlands.
Front Neurol. 2023 Jun 2;14:1136046. doi: 10.3389/fneur.2023.1136046. eCollection 2023.
Brain injury is a serious problem in patients who survive out-of-hospital cardiac arrest (OHCA). Neuroprotective drugs could reduce hypoxic-ischemic reperfusion injury. The aim of this study was to investigate the safety, tolerability, and pharmacokinetics (PK) of 2-iminobiotin (2-IB), a selective inhibitor of neuronal nitric oxide synthase.
Single-center, open-label dose-escalation study in adult OHCA patients, investigating three 2-IB dosing schedules (targeting an AUC of 600-1,200 ngh/m in cohort A, of 2,100-3,300 ngh/mL in cohort B, and 7,200-8,400 of ng*h/mL in cohort C). Safety was investigated by monitoring vital signs until 15 min after study drug administration and adverse events up to 30 days after admission. Blood sampling for PK analysis was performed. Brain biomarkers and patient outcomes were collected 30 days after OHCA.
A total of 21 patients was included, eight in cohort A and B and five in cohort C. No changes in vital signs were observed, and no adverse events related to 2-IB were reported. A two-compartment PK model described data the best. Exposure in group A (dosed on bodyweight) was three times higher than targeted (median AUC 2,398 ngh/mL). Renal function was an important covariate; therefore, in cohort B, dosing was performed on eGFR on admission. In cohort B and C, the targeted exposure was met (median AUC 2,917 and 7,323 ngh/mL, respectively).
The administration of 2-IB to adults after OHCA is feasible and safe. PK can be well predicted with correction for renal function on admission. Efficacy studies with 2-IB after OHCA are needed.
脑损伤是院外心脏骤停（OHCA）存活患者面临的一个严重问题。神经保护药物可减轻缺氧缺血再灌注损伤。本研究旨在调查神经元型一氧化氮合酶的选择性抑制剂2-亚氨基生物素（2-IB）的安全性、耐受性和药代动力学（PK）。
在成年OHCA患者中进行单中心、开放标签剂量递增研究，研究三种2-IB给药方案（队列A的目标AUC为600 - 1200 ngh/mL，队列B为2100 - 3300 ngh/mL，队列C为7200 - 8400 ng*h/mL）。通过监测给药后15分钟内的生命体征以及入院后30天内的不良事件来研究安全性。进行血样采集以进行PK分析。在OHCA发生30天后收集脑生物标志物和患者预后情况。
共纳入21例患者，队列A和B各8例，队列C 5例。未观察到生命体征变化，也未报告与2-IB相关的不良事件。二室PK模型对数据拟合最佳。A组（按体重给药）的暴露量比目标值高3倍（中位AUC为2398 ngh/mL）。肾功能是一个重要的协变量；因此，在队列B中，根据入院时的估算肾小球滤过率（eGFR）给药。在队列B和C中，达到了目标暴露量（中位AUC分别为2917和7323 ngh/mL）。
OHCA后对成人给予2-IB是可行且安全的。入院时校正肾功能可很好地预测PK。OHCA后使用2-IB的疗效研究是必要的。
