A Phase I Study of the Pharmacokinetics and Pharmacodynamics of Intranasal Doxylamine in Subjects with Chronic Intermittent Sleep Impairment
| Autor: | Mark Allison, Cecilia Hale |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Adult
Male Adolescent medicine.medical_treatment Cmax Administration Oral Biological Availability Nasal congestion Doxylamine Succinate 030226 pharmacology & pharmacy Young Adult 03 medical and health sciences 0302 clinical medicine Pharmacokinetics Sleep Initiation and Maintenance Disorders medicine Humans Metered Dose Inhalers Original Research Article Administration Intranasal Pharmacology Cross-Over Studies Dose-Response Relationship Drug Doxylamine business.industry Middle Aged Crossover study Nasal spray Pharmacodynamics Anesthesia Histamine H1 Antagonists Female medicine.symptom business 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Drugs in R&D |
| ISSN: | 1179-6901 1174-5886 |
| Popis: | 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 (Cmax) 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, Cmax 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. |
| Databáze: | OpenAIRE |
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