背景:肌内(IM)咪达唑仑可用于治疗癫痫持续状态。给药必须有效地快速终止长时间的癫痫发作并预防并发症。这项研究的目的是比较,在相对生物利用度和生物等效性方面,无针自动注射器注射咪达唑仑,在不同的设置中,通过常规注射器和针头注射IM咪达唑仑。
方法:在此开放标签中,随机化,四期交叉研究,健康成人在禁食条件下接受单剂咪达唑仑(10mg).参考治疗(常规注射器)给药一次,在大腿裸露的皮肤上.测试治疗(无针自动注射器ZENEO®)三次:大腿裸露皮肤,在臀板区域裸露的皮肤上,穿过大腿上的衣服。收集重复的血浆样品以获得36小时的药代动力学(PK)曲线。主要PK参数是血浆浓度-时间曲线下的面积,从时间零到最后一个可测量的时间点(AUC0-t),从时间零到无穷大(AUC0-∞),和观察到的最大血浆浓度(Cmax)。
结果:40名成年人被纳入PK分析集。在所有比较中,AUC0-t和AUC0-∞的最小二乘几何平均比的90%置信区间(CI)在80-125%的生物等效性范围内,个体内部变异系数低(所有比较中的所有参数<20.5%)。在所有比较中,Cmax也符合生物等效性,除了通过衣服比较测试的治疗与参考治疗。其中90%CI下限略超出生物等效性范围(78.8%)。在所有测试的治疗中,Cmax略低,但与参考治疗相比,早期平均血浆浓度(给药后前10分钟)较高.总的来说,所有的治疗都有很好的耐受性,最大镇静0.5-1小时后注射。
结论:本研究表明,使用ZENEO®在大腿裸露皮肤上注射IM咪达唑仑与使用注射器和针头注射IM咪达唑仑是生物等效的。可接受的相对生物利用度,与应急实践兼容,也显示在多个设置中。使用ZENEO®装置的前10分钟内平均浓度较高,更快的两步注射表明更快的作用开始,从而提前终止癫痫发作,从而防止长期癫痫发作和神经系统并发症的发生。
■ClinicalTrials.gov标识符:NCT05026567。注册首次发布于2021年8月30日,首例患者于2022年5月9日注册。
当癫痫发作持续超过5分钟时,需要紧急治疗。的确,当延长时,癫痫发作会对大脑造成损害,昏迷,最终死亡。在肌肉中注射咪达唑仑(即,肌内(IM)注射)已成为长期癫痫发作的首选一线治疗方法,通常使用注射器和30毫米针头给药。ZENEO®无针自动注射器是一种创新,预填充,单剂量,一次性的,随时可用,两步装置可以成为咪达唑仑IM给药的替代方法。因此,本研究比较了使用ZENEO®自动注射器的咪达唑仑IM注射与使用常规注射器和针头的IM注射。ZENEO®自动注射器在不同的条件下进行了测试(在裸露的皮肤上,通过服装,在大腿上,和臀部)在健康的志愿者中。研究表明,通过药代动力学分析(药物在血液中服用的速度和多少),咪达唑仑的吸收在所有测试条件下都是相似的,表明ZENEO®自动注射器是咪达唑仑给药的合适方法。此外,研究表明,在注射的前10分钟,当使用ZENEO®自动注射器进行注射时,血液中咪达唑仑的含量似乎更高,这表明如果注射该装置,癫痫发作治疗可能会更快开始起作用。这在紧急情况和院前设置中特别重要和相关,以防止持久的癫痫发作和对大脑的不可逆损害(当危机持续30分钟时可能发生)并最终改善患者的预后。
BACKGROUND: Intramuscular (IM) midazolam is indicated for the treatment of status epilepticus. Administration must be efficient to rapidly terminate prolonged seizures and prevent complications. The objective of this
study was to compare, in terms of relative bioavailability and bioequivalence, IM
midazolam injection by needle-free auto-injector, in different settings, to IM
midazolam injection by a conventional syringe and needle.
METHODS: In this open-label, randomized, four-period crossover study, healthy adults received single doses of midazolam (10 mg) under fasting conditions. The reference treatment (conventional syringe) was administered once, on bare skin in the thigh. The tested treatment (the needle-free auto-injector ZENEO®) was administered three times: on bare skin in the thigh, on bare skin in the ventrogluteal area, and through clothing in the thigh. Repeated plasma samples were collected to obtain 36-h pharmacokinetic (PK) profiles. Primary PK parameters were area under the plasma concentration-time curve, from time zero to the last measurable time point (AUC0-t) and from time zero to infinity (AUC0-∞), and the maximum observed plasma concentration (Cmax).
RESULTS: Forty adults were enrolled and included in the PK analysis set. In all comparisons, the 90% confidence interval (CI) of the least-squares geometric mean ratios for AUC0-t and AUC0-∞ were within the bioequivalence range of 80-125%, with low intra-individual coefficients of variation (< 20.5% for all parameters in all comparisons). Bioequivalence was also met for Cmax in all comparisons except when comparing the tested treatment through clothing versus the reference treatment, where the 90% CI lower limit was slightly outside the bioequivalence range (78.8%). With all tested treatments Cmax was slightly lower, but early mean plasma concentrations (first 10 min post-dosing) were higher when compared to the reference treatment. In general, all treatments were well tolerated, with maximum sedation 0.5-1 h post-injection.
CONCLUSIONS: This
study establishes that IM
midazolam injection on bare skin in the thigh with the ZENEO® is bioequivalent to IM midazolam injection with a syringe and needle. An acceptable relative bioavailability, compatible with emergency practice, was also shown in multiple settings. Higher mean concentrations within the first 10 min with the ZENEO® device, and quicker two-step injection suggest a faster onset of action, and thereby an earlier seizure termination, thus preventing the occurrence of prolonged seizure and neurological complications.
UNASSIGNED: ClinicalTrials.gov identifier: NCT05026567. Registration first posted August 30, 2021, first patient enrolled May 9, 2022.
Seizures require urgent treatment when they last longer than 5 min. Indeed, when prolonged, seizures can lead to damage to the brain, coma, and ultimately death. Midazolam injected in the muscle (i.e., intramuscular (IM) injection) has become the first-line treatment of choice for long-lasting seizures and is usually administered with a syringe and 30-mm needle. The ZENEO® needle-free auto-injector is an innovative, pre-filled, single-dose, disposable, ready-to-use, two-step device that could become an alternative method for midazolam IM administration. This
study therefore compared
midazolam IM injections with the ZENEO® auto-injector versus IM injections with a conventional syringe and needle. The ZENEO® auto-injector was tested in different conditions (on bare skin, through clothing, in the thigh, and in the hip) in healthy volunteers. The study showed, with a pharmacokinetic analysis (how much and how fast a drug is taken in the bloodstream), that midazolam absorption was similar in all tested conditions, indicating that the ZENEO® auto-injector is a suitable method for midazolam administration. In addition, the
study showed that in the first 10 min of the injection, the amount of
midazolam in the blood seemed to be higher when injections were performed with the ZENEO® auto-injector, suggesting that seizure treatment may start working sooner if injected with the device. This is particularly important and relevant in emergency situations and prehospital settings in order to prevent long-lasting seizures and irreversible damage to the brain (which can occur when a crisis lasts for 30 min) and ultimately improve the patient’s outcome.