title: Assessment of pharmacokinetics and tolerability of intranasal diazepam relative to rectal gel in healthy adults.
abstract: Diazepam rectal gel (RG) is currently the only approved rescue therapy for outpatient management of seizure clusters in the United States. There is an unmet medical need for an alternative rescue therapy for seizure clusters that is effective, and more convenient to administer with a socially acceptable method of delivery. An intranasal diazepam formulation has been developed, and this study evaluates the tolerability and bioavailability of diazepam nasal spray (NS) relative to an equivalent dose of diazepam-RG in healthy adults. Twenty-four healthy adults were enrolled in a phase 1, open-label, 3-period crossover study. Plasma diazepam and metabolite concentrations were measured by serial sampling. Dose proportionality for 5- and 20-mg intranasal doses and the bioavailability of 20mg diazepam-NS relative to 20mg diazepam-RG were assessed by maximum plasma concentration (Cmax) and systemic exposure parameters (AUC0-∞ and AUC0-24). The mean Cmax values for 20mg diazepam-NS and 20mg diazepam-RG were 378 ± 106 and 328 ± 152 ng/mL, achieved at 1.0 and 1.5h, respectively. Subjects administered intranasal and rectal gel formulations experienced nasal and rectal leakage, respectively. Diazepam absorption following intranasal administration was consistent but 3 subjects with diazepam-RG had low plasma drug levels at the earliest assessment of 5 min, due to poor retention, and were excluded from analysis. Excluding them, the treatment ratios (20mg diazepam-NS:20mg diazepam-RG) and 90% confidence intervals for diazepam Cmax and AUC0-24 were 0.98 (0.85-1.14) and 0.89 (0.80-0.98), respectively, suggesting that the bioavailability was comparable between the two formulations. Dose proportionality was observed between the lowest and highest dose-strengths of intranasal formulation. Both intranasal and rectal treatments were well tolerated with mild to moderate adverse events. Results suggest that a single-dose of 20mg diazepam-NS is tolerable and comparable in bioavailability to that of diazepam-RG. The intranasal formulation may provide caregivers and patients with a more socially acceptable and convenient alternative rescue therapy in the acute treatment of seizure clusters.
authors.affiliation: Acorda Therapeutics, Inc., 420 Saw Mill River Road, Ardsley, NY 10502, USA.
authors.forename: Herbert R
authors.initials: HR
authors.lastname: Henney
authors.affiliation: Department of Neurology, Thomas Jefferson University, 901 Walnut Street, Suite 400, Philadelphia, PA 19107, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Sperling
authors.affiliation: Acorda Therapeutics, Inc., 420 Saw Mill River Road, Ardsley, NY 10502, USA. Electronic address: arabinowicz@acorda.com.
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Rabinowicz
authors.affiliation: Aerial BioPharma, LLC, 9001 Aerial Center Parkway, Suite 110, Morrisville, NC 27560, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Bream
authors.affiliation: Acorda Therapeutics, Inc., 420 Saw Mill River Road, Ardsley, NY 10502, USA.
authors.forename: Enrique J
authors.initials: EJ
authors.lastname: Carrazana
mesh_terms: D000281:Administration, Intranasal; D000285:Administration, Rectal; D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D000927:Anticonvulsants / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D001682:Biological Availability; D018592:Cross-Over Studies; D003975:Diazepam / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D053719:Tandem Mass Spectrometry; D013997:Time Factors; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D003975:Diazepam
keywords: Adults; Diazepam; Intranasal; Pharmacokinetics; Seizures