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

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.

Dexmedetomidine nasal administration improves perioperative sleep quality and neurocognitive deficits in elderly patients undergoing general anesthesia

“…The reason may be related to the drug action and administration method of dexmedetomidine. On the one hand, dexmedetomidine has a certain analgesic effect, reducing pain induced hypertension in patients; On the other hand, dexmedetomidine administered through the nasal cavity has a slow onset rate and avoids adverse reactions such as blood pressure drop and bradycardia caused by intravenous injection [ 30 ]. Dexmedetomidine has a better postoperative sedative and analgesic effect.…”

Clinical observation of dexmedetomidine nasal spray in the treatment of sleep disorders on the first night after undergoing maxillofacial surgery: a single-center double-blind randomized controlled study

“…The doses were safe and effective. Using the optimized nasal spray method can greatly improve the bioavailability of the test drug in healthy adults [ 25 ]. Intranasal administration of 1.0 μg/kg dexmedetomidine is reportedly more effective than buccal administration of 1.0 μg/kg dexmedetomidine for premedication in children [ 26 ].…”

Safety and Efficacy of Dexmedetomidine Nasal Spray for Pre-anaesthetic Sedation in Children: A Randomised, Double-Blinded, and Placebo-Controlled Trial

“…By producing ne small particles, the spray is expected to have less drug loss, increased bioavailability, and improved compatibility as compared with drops [14]. Previous studies demonstrated that the bioavailability of dexmedetomidine nasal spray was higher than that of nasal drops [13,15].…”

“…This nasal spray was administered directly with no need of dilution or con guration before use. We previously evaluated its safety and tolerability, pharmacokinetics, and pharmacodynamics in healthy adults [15] and children undergoing elective surgery under general anaesthesia (NCT04200235). Its effectiveness and favorable safety pro le have been demonstrated in the adult pre-anaesthetic sedation setting in a pivotal phase 3 study (NCT04383418).…”