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 (IN) midazolam formulation, to a 2.5-mg intravenous (IV) 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 IN 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 IV dose. PD responses were rapid, paralleled the PK, and in magnitude was in a rank order of IV 2.5 mg ≥ IN 5.0 mg > IN 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 IN midazolam formulation resulted in rapid absorption and attained plasma concentrations that correlated with pharmacodynamic effects.