R Edward Hogan1, Barry E Gidal2, Barry Koplowitz3, Luana P Koplowitz3, Richard E Lowenthal4, Enrique Carrazana5. 1. Department of Neurology, Washington University in St Louis School of Medicine, St Louis, Missouri. 2. School of Pharmacy, University of Wisconsin, Madison, Wisconsin. 3. DUCK FLATS Pharma, Elbridge, New York. 4. Pacific Link Consulting, San Diego, California. 5. Consultant for Neurelis, Miami, Florida.
Abstract
OBJECTIVE: The study assesses the bioavailability of diazepam after intranasal administration (diazepam nasal spray) in healthy volunteers. Comparative agents were diazepam rectal gel, which served as the regulatory reference product; and oral diazepam, a product with decades of clinical use. Tolerability of diazepam nasal spray was also assessed. METHODS: This was a phase 1, open-label, randomized, single-dose, three-treatment, three-period, six-sequence crossover study in 48 healthy adult subjects that consisted of a screening period, a baseline period, and an open-label treatment period. Interperiod intervals were at least 28 days. RESULTS:Forty-eight healthy volunteer subjects were enrolled, two of whom discontinued before receiving study medication. For all routes of administration, the onset of diazepam absorption was rapid, with measurable concentrations of drug present by the first sample time point. The tmax (time to reach maximum plasma concentration) was similar for diazepam nasal spray and diazepam rectal gel, both of which were slower than oral diazepam in fasted individuals. Variability (as defined by % coefficient of variation of geometric mean) in peak plasma concentration and area under the curve0-∞ was lowest with oral diazepam, followed by diazepam nasal spray, with diazepam rectal gel showing the greatest variability. Overall, 131 treatment-emergent adverse events (TEAEs) were considered mild (42 subjects, 91.3%), four TEAEs were considered moderate (four subjects, 8.3%), and no TEAEs were considered severe. The most commonly reported TEAE was somnolence at 56.5% (26/46) during diazepam nasal spray treatment, 89.1% (41/46) with the rectal diazepam gel treatment, and 82.6% (38/46) with oral diazepam treatment. No nasal irritation was observed for the majority of the subjects at any time point after administration, with no score higher than 2 ("minor bleeding that stops within 1 minute"). SIGNIFICANCE: Diazepam nasal spray shows predicable pharmacokinetics and represents a potential novel therapeutic approach to control bouts of increased seizure activity (cluster seizures, acute repetitive seizures).
RCT Entities:
OBJECTIVE: The study assesses the bioavailability of diazepam after intranasal administration (diazepam nasal spray) in healthy volunteers. Comparative agents were diazepam rectal gel, which served as the regulatory reference product; and oral diazepam, a product with decades of clinical use. Tolerability of diazepam nasal spray was also assessed. METHODS: This was a phase 1, open-label, randomized, single-dose, three-treatment, three-period, six-sequence crossover study in 48 healthy adult subjects that consisted of a screening period, a baseline period, and an open-label treatment period. Interperiod intervals were at least 28 days. RESULTS: Forty-eight healthy volunteer subjects were enrolled, two of whom discontinued before receiving study medication. For all routes of administration, the onset of diazepam absorption was rapid, with measurable concentrations of drug present by the first sample time point. The tmax (time to reach maximum plasma concentration) was similar for diazepam nasal spray and diazepam rectal gel, both of which were slower than oral diazepam in fasted individuals. Variability (as defined by % coefficient of variation of geometric mean) in peak plasma concentration and area under the curve0-∞ was lowest with oral diazepam, followed by diazepam nasal spray, with diazepam rectal gel showing the greatest variability. Overall, 131 treatment-emergent adverse events (TEAEs) were considered mild (42 subjects, 91.3%), four TEAEs were considered moderate (four subjects, 8.3%), and no TEAEs were considered severe. The most commonly reported TEAE was somnolence at 56.5% (26/46) during diazepam nasal spray treatment, 89.1% (41/46) with the rectal diazepam gel treatment, and 82.6% (38/46) with oral diazepam treatment. No nasal irritation was observed for the majority of the subjects at any time point after administration, with no score higher than 2 ("minor bleeding that stops within 1 minute"). SIGNIFICANCE: Diazepam nasal spray shows predicable pharmacokinetics and represents a potential novel therapeutic approach to control bouts of increased seizure activity (cluster seizures, acute repetitive seizures).
Authors: James W Wheless; Ian Miller; R Edward Hogan; Dennis Dlugos; Victor Biton; Gregory D Cascino; Michael R Sperling; Kore Liow; Blanca Vazquez; Eric B Segal; Daniel Tarquinio; Weldon Mauney; Jay Desai; Adrian L Rabinowicz; Enrique Carrazana Journal: Epilepsia Date: 2021-08-21 Impact factor: 6.740
Authors: Adam Strzelczyk; Laurent M Willems; Ricardo Kienitz; Lara Kay; Isabelle Beuchat; Sarah Gelhard; Sophie von Brauchitsch; Catrin Mann; Alexandra Lucaciu; Jan-Hendrik Schäfer; Kai Siebenbrodt; Johann-Philipp Zöllner; Susanne Schubert-Bast; Felix Rosenow Journal: CNS Drugs Date: 2022-08-16 Impact factor: 6.497
Authors: Robert Edward Hogan; Daniel Tarquinio; Michael R Sperling; Pavel Klein; Ian Miller; Eric B Segal; Adrian L Rabinowicz; Enrique Carrazana Journal: Epilepsia Date: 2020-04-27 Impact factor: 5.864
Authors: Ian Miller; James W Wheless; Robert E Hogan; Dennis Dlugos; Victor Biton; Gregory D Cascino; Michael R Sperling; Kore Liow; Blanca Vazquez; Eric B Segal; Daniel Tarquinio; Weldon Mauney; Jay Desai; Adrian L Rabinowicz; Enrique Carrazana Journal: Epilepsia Open Date: 2021-05-13