Bioavailability and Safety of a New Highly Concentrated Midazolam Nasal Spray Compared to Buccal and Intravenous Midazolam Treatment in Chinese Healthy Volunteers

Abstract

Introduction: Buccal midazolam treatment is licensed in the European Union for prolonged acute convulsive seizures in children and adolescents, but the buccal pathway is often hampered by jaw clenching, hypersalivation, or uncontrolled swallowing. Midazolam formulations that are more secure, reliable, and faster for use are needed in the acute setting. Pharmacokinetics and comparative bioavailability of intranasally administered midazolam and two midazolam intravenous solutions administered buccally or intravenously in healthy adults were evaluated.Methods: In this phase 1, open-label, randomized, single-dose, three-period, three-sequence crossover study, 12 healthy adults (19-41 years) were randomly assigned to receive 2.5 mg midazolam intranasally; 2.5 mg midazolam intravenously; 2.5 mg midazolam buccally. Blood samples were collected for 10 h post dose to determine pharmacokinetic profiles. Adverse events and vital signs were recorded. Results: Intranasal administration of 2.5 mg midazolam demonstrated a more rapid median time to C max compared to buccal administration of midazolam (T max , 12.6 min vs. 45 min; C max , 38.33 ng/ml vs. 24.97 ng/ml). The antiepileptic effect of intranasal and buccal midazolam treatment lasted less than 4 h and generally did not differ from intravenously administered midazolam. No serious adverse events or deaths were reported, and no treatment-emergent adverse events led to study discontinuation. Conclusion:Intranasal administration of midazolam may be a preferable alternative to the currently approve buccal midazolam treatment for prolonged acute convulsive seizures in children and adolescents.Trial Registration: This study is registered at the Chinese Clinical Trial [http://www.chictr. org.cn] (ChiCTR2000032595) on 3 May, 2020.

Effect of intranasal and oral administration of levetiracetam on the temporal and spatial distributions of SV2A in the KA‐induced rat model of SE

“…To date, most of the investigations on nasal administration of AEDs are focused on the pharmacokinetics, while the studies on the efficacy of AEDs are sparse 29–31 . Recent studies have used the intravenous administration of medicines to compare the effects with those of the nasal administration 32,33 . Our study was novel in its connection between the nasal administration of LEV and the LEV binding site in the brain tissue as well as the molecular mechanisms underlying the therapeutic effects of LEV in the treatment of epilepsy, revealing the similar efficacy of nasal and oral administrations of LEV.…”

“… 29 , 30 , 31 Recent studies have used the intravenous administration of medicines to compare the effects with those of the nasal administration. 32 , 33 Our study was novel in its connection between the nasal administration of LEV and the LEV binding site in the brain tissue as well as the molecular mechanisms underlying the therapeutic effects of LEV in the treatment of epilepsy, revealing the similar efficacy of nasal and oral administrations of LEV. These consistent findings between the nasal and oral administrations of LEV were likely due to the time of administration selected in this study.…”