Pharmacokinetics and tolerability of intranasal diazepam and midazolam in healthy adult volunteers.
OBJECTIVE
The purpose of this pilot study was to determine the pharmacokinetics and tolerability of an investigational diazepam (DZP) formulation and a parenteral midazolam (MDZ) formulation following intranasal (i.n.) administration for the efficient treatment of seizure emergencies.


METHODS
Each subject received 5 mg of DZP and MDZ via both i.n. and intravenous routes in a four-way, randomized crossover trial. Blood samples were collected over 48 h. DZP and MDZ concentrations were measured using HPLC. Using analog scales, subjects rated tolerability (0 = no change from normal; 10 = maximum intolerability) and pain (0 = no pain; 4 = extreme pain) prior to and 0, 5, 15, 60 min, and 8 h after administration.


RESULTS
The C(max) and T(max) values for i.n. DZP and MDZ were 179.2 ng/ml and 28.8 min vs 62.8 ng/ml and 21.6 min, respectively. Immediately following i.n. administration, subjects reported tolerability scores of 6.75 and 6.0, and identical pain scores, 3.2, for DZP and MDZ, respectively.


CONCLUSIONS
Both formulations were rapidly absorbed following i.n. administration with transient discomfort. DZP had a longer half-life, which may result in an extended duration of action. Further studies in large patient populations to evaluate the safety after long term use, efficacy and pharmacokinetics of i.n. DZP are warranted.
Ivaturi
V D
VD
Center for Orphan Drug Research, University of Minnesota, Minnesapolis, MN 55455, USA.
Riss
J R
JR
Kriel
R L
RL
Cloyd
J C
JC
D000281:Administration, Intranasal; D000927:Anticonvulsants / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D003975:Diazepam / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D005260:Female; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D008874:Midazolam / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D010147:Pain Measurement; D018579:Patient Selection; D010865:Pilot Projects; D016037:Single-Blind Method; D013997:Time Factors; D055815:Young Adult
D000927:Anticonvulsants; D003975:Diazepam; D008874:Midazolam