Phase I Clinical Trial Unit, The First Affiliated Hospital with Nanjing Medical University, #300 Guangzhou Road, Nanjing, 210029, Jiangsu, China.
Department of Clinical Pharmacology, Pharmacy College, Nanjing Medical University, Nanjing, 211166, China.
Clin Drug Investig. 2023 Jun;43(6):421-433. doi: 10.1007/s40261-023-01276-5. Epub 2023 Jun 4.
Midazolam rectal gel is a novel rectal formulation that may be a promising and potential alternative to oral administration for pediatric sedation. The objective of this study was to evaluate the safety, pharmacokinetics, pharmacodynamics, and absolute bioavailability of midazolam rectal gel in healthy Chinese subjects.
An open-label, single-dose, randomized, two-period, two-treatment, crossover clinical study was conducted in 22 healthy subjects (16 males and six females), each receiving 2.5 mg intravenous midazolam in one period and 5 mg midazolam rectal gel in another period (the dosages here were calculated as active midazolam). Safety, pharmacokinetic, and pharmacodynamic assessments were conducted throughout the study.
All of the subjects completed both treatment periods. The formulation of rectal gel was well tolerated, with no serious adverse events occurring. After a single rectal dose of 5 mg midazolam rectal gel, it was absorbed rapidly with a median value of time to peak concentration (T) of 1.00 h, and mean values of the peak concentration (C) and area under the concentration-time curve (AUC) of 37.2 ng/mL and 137 h·ng/mL, respectively. The absolute bioavailability of rectal gel was 59.7%. The rectal gel exhibited a relatively delayed onset but a more stable sedative effect and a longer duration when compared with intravenous midazolam.
Midazolam rectal gel may be a feasible alternative with a high level of acceptance in pediatric sedation and enhanced bioavailability compared to an oral formulation. The modeling results may help to disclose out the exposure-response relationship of midazolam rectal gel and support the design of an escalating-doses study and pediatric extrapolation study.
The study was registered at http://www.chinadrugtrials.org.cn (No. CTR20192350).
咪达唑仑直肠凝胶是一种新型直肠制剂，可能是儿科镇静的一种有前途和潜在的口服替代选择。本研究的目的是评估咪达唑仑直肠凝胶在健康中国受试者中的安全性、药代动力学、药效学和绝对生物利用度。
一项开放标签、单剂量、随机、两周期、两治疗、交叉临床试验在 22 名健康受试者（16 名男性和 6 名女性）中进行，每名受试者在一个周期内接受 2.5mg 咪达唑仑静脉注射，另一个周期内接受 5mg 咪达唑仑直肠凝胶（此处剂量计算为活性咪达唑仑）。整个研究过程中进行了安全性、药代动力学和药效学评估。
所有受试者均完成了两个治疗期。直肠凝胶制剂耐受性良好，无严重不良事件发生。单次直肠剂量 5mg 咪达唑仑直肠凝胶后，吸收迅速，达峰时间（T）中位数为 1.00 小时，峰浓度（C）和浓度-时间曲线下面积（AUC）均值分别为 37.2ng/ml 和 137h·ng/ml。直肠凝胶的绝对生物利用度为 59.7%。与静脉咪达唑仑相比，直肠凝胶起效相对延迟，但镇静效果更稳定，作用持续时间更长。
与口服制剂相比，咪达唑仑直肠凝胶在儿科镇静中可能是一种可行的替代选择，具有较高的接受度和更高的生物利用度。模型结果可能有助于揭示咪达唑仑直肠凝胶的暴露-反应关系，并支持递增剂量研究和儿科外推研究的设计。
