Kuang Yun, Wang Sai-Ying, Wang Meng-Na, Yang Guo-Ping, Guo Can, Yang Shuang, Zhang Xing-Fei, Yang Xiao-Yan, Pei Qi, Zou Chan, He Yan-Hong, Zhou Ying-Yong, Duan Kai-Ming, Huang Jie
Center for Clinical Pharmacology, The Third Xiangya Hospital of Central South University, Changsha, China.
Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha, China.
Front Pharmacol. 2022 May 20;13:871492. doi: 10.3389/fphar.2022.871492. eCollection 2022.
The present study evaluated the safety, pharmacokinetics/pharmacodynamics (PK/PD), and absolute bioavailability (Fabs) of Dex nasal spray in healthy adult subjects, which serves as a bridge for the subsequent study in children. Part 1: a double-blind, placebo-controlled, single ascending dose study was performed on 48 subjects. For 20-/40-μg groups, every 6/2 subjects received either Dex/placebo nasal spray or Dex/placebo injection in two periods. In total, 12/4 subjects each received 100 μg Dex/placebo nasal spray. Part 2: a randomized, double-blind, placebo-controlled study; 12/4 subjects received 150 μg Dex/placebo nasal spray. Part 3: a randomized, open, self-crossover study; 12 subjects received 20 μg and 100 μg Dex nasal spray in two periods alternately. The method of administration was optimized in Part 2 and Part 3. In part 1, Dex nasal spray was well tolerated up to the maximum dose of 100 μg, whereas the Fabs was tolerated to only 28.9%-32.3%. In Part 2 and Part 3, the optimized nasal spray method was adopted to promote the Fabs of Dex nasal spray to 74.1%-89.0%. A severe adverse event was found in Part 2. In Part 3 (100 μg), the Ramsay score increased the most and lasted the longest, whereas the BIS score decreased most significantly. Using the optimized nasal spray method, a single dose of 20/100 μg of the test drug was safe and tolerable, and 100 μg may have approached or reached the plateau of sedation. In addition, it is found that the optimized method can greatly improve the bioavailability of the test drug, leading to its higher reference value.
本研究评估了右美托咪定鼻喷雾剂在健康成年受试者中的安全性、药代动力学/药效学（PK/PD）及绝对生物利用度（Fabs），为后续儿童研究搭建桥梁。第1部分：对48名受试者进行了一项双盲、安慰剂对照、单剂量递增研究。对于20/40μg组，每6/2名受试者在两个阶段分别接受右美托咪定/安慰剂鼻喷雾剂或右美托咪定/安慰剂注射液。总共12/4名受试者各自接受了100μg右美托咪定/安慰剂鼻喷雾剂。第2部分：一项随机、双盲、安慰剂对照研究；12/4名受试者接受了150μg右美托咪定/安慰剂鼻喷雾剂。第3部分：一项随机、开放、自身交叉研究；12名受试者在两个阶段交替接受20μg和100μg右美托咪定鼻喷雾剂。在第2部分和第3部分对给药方法进行了优化。在第1部分中，右美托咪定鼻喷雾剂在高达100μg的最大剂量下耐受性良好，而Fabs仅为28.9%-32.3%。在第2部分和第3部分中，采用了优化的鼻喷雾剂方法，将右美托咪定鼻喷雾剂的Fabs提高到74.1%-89.0%。在第2部分中发现了1例严重不良事件。在第3部分（100μg）中，Ramsay评分升高幅度最大且持续时间最长，而BIS评分下降最为显著。采用优化的鼻喷雾剂方法，单剂量20/100μg受试药物安全且耐受性良好，100μg可能已接近或达到镇静平台期。此外，发现优化方法可大幅提高受试药物的生物利用度，具有较高的参考价值。
