Pharmacokinetics of a Novel Zolpidem Nasal Spray for Rapid Management of Insomnia: First Trial in Humans

Abstract

Study Objectives: The present single-dose, parallel-group, randomized, double-blind, placebo-controlled study is to evaluate the pharmacokinetics, tolerability and safety of zolpidem tartrate nasal spray (ZNS) as compared to placebo in healthy subjects. Methods: Thirty-six healthy subjects participated in this study, with 19 male and 17 female subjects in 3 cohorts (12 subjects per cohort), who were randomly assigned to receive either an intranasal dose of ZNS 1.75 mg, 3.5 mg, 5.0 mg (n = 10 per dose), or an intranasal placebo (n = 2). Multiple venous blood samples were collected for pharmacokinetic analyses. Results: Plasma zolpidem concentrations rapidly increased after intranasal ZNS 1.75, 3.5, and 5.0 mg with mean T max of 0.42, 0.76 and 0.50 h, respectively, followed by rapid decreases at all three doses. C max , AUC 0-t , and AUC 0-∞ were found to increase in a dose-proportional manner. Female subjects had generally higher AUC 0-t , AUC 0-∞ , and lower weight-normalized clearance rate (CL/F) than male subjects. In this study, ZNS was safe and well tolerated over the evaluated dose range. There were no serious adverse events. Conclusions: Zolpidem was rapidly absorbed and eliminated after intranasal administration of ZNS. Dose proportionality was found at the doses ranged from 1.75 mg to 5.0 mg. Intranasal exposure of zolpidem was generally higher in female subjects than that in male subjects. It could be concluded that ZNS is safe and well tolerated over the evaluated range of intranasal doses. Keywords: insomnia, middle-of-the-night awakening, hypnotics, pharmacokinetics, drug metabolism Citation: Li CT, Su TP, Wang Y, Lee B, Toh M, Ho T. Pharmacokinetics of a novel zolpidem nasal spray for rapid management of insomnia: first trial in humans.

Bioequivalence of zolpidem hemitartrate: new formulations of 5 mg SL, 10 mg and 12.5 mg XR and comparison of their bioavailabilities

“…Forty study subjects were to participate in this study in order to meet the requirements of nominal significance level of 50 %, 2x2 crossover design, 80-125% equivalence range, 28% maximum CVintra for pharmacokinetic parameters, population ratio between 95-105% for treatment average plus an additional number of 8 volunteers to compensate possible losses due to dropout/exclusions. The planned number of subjects for the study is consistent with studies reported buy some authors [29][30][31] and higher than the number estimated by other [10,32]. The study was completed with 38 subjects, an amount higher than the 32 estimated volunteers in case of loss of the 8 subjects considered in the sample size determination, fact which contributed to maintain the obtained test power for pharmacokinetic parameters near 100%.…”

Comparative bioavailability of two zolpidem hemitartrate formulations in healthy human Brazilian volunteers using high‐performance liquid chromatography coupled to tandem mass spectrometry

“…bioavailability, LC/MS/MS, pharmacokinetics, tandem mass spectrometry 1 | INTRODUCTION Zolpidem, a benzodiazepine receptor agonist, is a hypnosedative imidazopyridine that has a strong sedative action with minor anxiolytic, muscle relaxant or anticonvulsant properties. Zolpidem decreases the time to sleep onset and increases duration of sleep with effects on sleep stages (Greenblatt & Roth, 2012;Hoehns & Perry, 1993;Holm & Goa, 2000;Langtry & Benfield, 1990;Li et al, 2016;Salva & Costa, 1995;Swainston Harrison & Keating, 2005). It is administered as an oral standard immediate release tablet (5 and 10 mg), oral controlled release tablet (6.25 and 12.5 mg) or sublingual tablet (5 and 10 mg) for difficulty with sleep onset.…”

“…It is administered as an oral standard immediate release tablet (5 and 10 mg), oral controlled release tablet (6.25 and 12.5 mg) or sublingual tablet (5 and 10 mg) for difficulty with sleep onset. The sublingual tablet (1.75 mg women; 3.5 mg for men) is indicated for middle-of-the-night wakefulness, oral spray (5 mg) for difficulty with sleep initiation and nasal spray (1.75 mg, 3.5 mg, 5.0 mg) for sleep initiation difficulty and middle-ofthe-night awakening (Greenblatt & Roth, 2012;Hoehns & Perry, 1993;Holm & Goa, 2000;Langtry & Benfield, 1990;Li et al, 2016;Neubauer, 2010;Pergolizzi, Taylor, Raffa, Nalamachu, & Chopra, 2014;Salva & Costa, 1995;Swainston Harrison & Keating, 2005). The pharmacokinetics of zolpidem by sublingual administration is influenced by food intake and gender (Greenblatt et al, 2013;Greenblatt et al, 2014;Li et al, 2016;Pergolizzi et al, 2014).…”