A Phase I Study of the Pharmacokinetics and Pharmacodynamics of Intranasal Doxylamine in Subjects with Chronic Intermittent Sleep Impairment

INTRODUCTION: Doxylamine tablets are approved as an over-the-counter sleep aid. We developed a doxylamine succinate intranasal metered-dose delivery system with the expectation of a more rapid onset of action with reduced side-effect potential compared with the oral tablet. METHODS: This phase I study randomized 24 adults with chronic intermittent sleep impairment to receive either single doses of intranasal doxylamine succinate 3.2, 6.3, or 12.7 mg or doxylamine succinate 25-mg oral tablet. Doxylamine pharmacokinetics were assessed using noncompartmental methods; pharmacodynamics were evaluated using the Karolinska Sleepiness Scale (KSS) and numerous psychomotor tests. Adverse events (AEs) were monitored. RESULTS: None of the intranasal dose levels produced a mean maximum plasma concentration (C(max)) above the 50 ng/mL target level or a time to maximum concentration shorter than that of the oral tablet. At the highest intranasal dose, C(max) and area under the doxylamine concentration–time curve were approximately 25% of the values achieved with the oral dose. Variation in most pharmacokinetic parameters was higher with intranasal compared with oral dosing. A relationship between plasma doxylamine concentration and KSS change from baseline was evident for the 25-mg tablet and, to a lesser extent, for the 12.7-mg intranasal dose. Changes from baseline in psychomotor parameters did not show a relationship to intranasal dose, and did not distinguish between intranasal versus oral dosing. The most common AEs with intranasal dosing were nasal congestion, nasal dryness, and frontal headache. CONCLUSION: The nasal spray did not increase doxylamine absorption or systemic bioavailability compared with the oral tablet.