title: Bioavailability and tolerability of intranasal diazepam in healthy adult volunteers.
abstract: Intranasal therapy has been proposed as an alternative for the management of seizure emergencies. The bioavailability, dose proportionality and tolerability of a supersaturated intranasal formulation of diazepam (DZP) solubilized in a glycofurol-water cosolvent system was investigated. Eight healthy volunteers were randomized into a single-blind, three-way crossover study to compare 5 and 10mg intranasal DZP doses of the investigational formulation with a 5mg dose of a DZP solution (DZP injectable, 5mg/mL) administered intravenously. Treatments were separated by a two-week washout period. Plasma samples for DZP analysis were collected pre-dose and at regular intervals up to 48h post-dose and assayed by HPLC. Visual analog scales (VAS) were used to assess tolerability (1-tolerable; 10-extremely intolerable) and pain (1-no pain; 4-extreme pain) at predefined time points. Following the 5 and 10mg doses, the median t(max) were 20 and 30min and the mean C(max) were 134.3+/-62 and 247.6+/-61ng/mL. Estimated bioavailability was 75% for both doses. Pain scores of 2 and 2.3 were observed following the 5 and 10mg doses; tolerability scores were 4.4 and 4.7. Pain and tolerability scores returned to baseline within 10h. Our formulation provided reasonable bioavailability, but was not well tolerated.
authors.affiliation: Center for Orphan Drug Research, University of Minnesota, Minneapolis, MN 55455, United States. ivatu001@umn.edu
authors.forename: Vijay D
authors.initials: VD
authors.lastname: Ivaturi
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Riss
authors.forename: Robert L
authors.initials: RL
authors.lastname: Kriel
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Siegel
authors.forename: James C
authors.initials: JC
authors.lastname: Cloyd
mesh_terms: D000281:Administration, Intranasal; D000328:Adult; D000927:Anticonvulsants / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D003975:Diazepam / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D016037:Single-Blind Method; D013997:Time Factors
chemical_list: D000927:Anticonvulsants; D003975:Diazepam