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. 2022 May 20:13:871492.
doi: 10.3389/fphar.2022.871492. eCollection 2022.

Safety, Pharmacokinetics/Pharmacodynamics, and Absolute Bioavailability of Dexmedetomidine Hydrochloride Nasal Spray in Healthy Subjects: A Randomized, Parallel, Escalating Dose Study

Yun Kuang  1 , Sai-Ying Wang  2 , Meng-Na Wang  1 , Guo-Ping Yang  1   3   4 , Can Guo  1 , Shuang Yang  1 , Xing-Fei Zhang  1 , Xiao-Yan Yang  1 , Qi Pei  4 , Chan Zou  1   3 , Yan-Hong He  2 , Ying-Yong Zhou  2 , Kai-Ming Duan  2 , Jie Huang  1   3
Affiliations

Safety, Pharmacokinetics/Pharmacodynamics, and Absolute Bioavailability of Dexmedetomidine Hydrochloride Nasal Spray in Healthy Subjects: A Randomized, Parallel, Escalating Dose Study

Yun Kuang et al. Front Pharmacol. .

Abstract

Background: 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. Methods: 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. Results: 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. Conclusion: 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.

Keywords: absolute bioavailability; dexmedetomidine nasal spray; healthy subjects; pharmacodynamics; pharmacokinetics.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer DSO declared a shared parent affiliation with the authors to the handling editor at the time of review.

Figures

FIGURE 1
FIGURE 1
Mean concentration–time curves of dexmedetomidine in healthy subjects following a single dose of dexmedetomidine nasal spray or injection. (A) Part 1, (B) Part 2, and Part 3. NS, nasal spray; IV, intravenous.
FIGURE 2
FIGURE 2
Change in BIS/RSS values compared with the baseline-time curves in healthy subjects after a single dose of dexmedetomidine nasal spray, injection, or placebo. (A), (B) Part 1. (C), (D) Part 2, and Part 3. BIS, bispectral index; RSS, Ramsay sedation score; NS, nasal spray; IV, intravenous.
FIGURE 3
FIGURE 3
Concentration–time curves of dexmedetomidine in healthy subjects following a single dose of dexmedetomidine nasal spray. (A) 20 μg in Part 3. (B) 100 μg in Part 3. (C) 150 μg in Part 2.
See this image and copyright information in PMC

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