A pharmacokinetic and pharmacodynamic study, in healthy volunteers, of a rapidly absorbed intranasal midazolam formulation.

PURPOSE: To compare 2.5 mg and 5.0 mg single-dose pharmacokinetics (PK), pharmacodynamics (PD) and tolerability of an intranasal (i.n.) midazolam formulation, to a 2.5-mg intravenous (i.v.) dose.
METHODS: Design was an open-label, three-way crossover, randomized PK and PD study in seventeen healthy volunteers. Twelve-hour PK parameters were determined for each treatment arm. Subjects completed serial self-ratings for sedation and other drug effects. Nurse observers made serial observations for sedation and adverse effects. An otolaryngologist conducted a nasal endoscopy, pre-dose, 2-4 h, and at end of study, to examine the nasal cavity for formulation-induced changes in nasal anatomy.
RESULTS: Midazolam was rapidly absorbed following i.n. administration, with a median t(max) of 10 min; dose proportionate increases for C(max) and AUC; t(1/2) of 4 h; and, 60% (+/-23) nasal administration bioavailability compared to the i.v. dose. PD responses were rapid, paralleled the PK, and in magnitude was in a rank order of i.v. 2.5 mg > or = i.n. 5.0 mg > i.n. 2.5 mg doses. The formulation was well tolerated with no serious cardiovascular or respiratory complications. Fourteen subjects complained of at least one of the following: a brief and mild to moderate intensity facial flushing, nasal passage burning, sore throat or bad taste after drug administration. There were no adverse findings from the nasal endoscopic exam.
CONCLUSION: Dosages of an investigational i.n. midazolam formulation resulted in rapid absorption and attained plasma concentrations that correlated with pharmacodynamic effects.

RCT Entities:   Population Interventions Outcomes