Gender differences in pharmacokinetics and pharmacodynamics of zolpidem following sublingual administration

Greenblatt, David J.; Harmatz, Jerold S.; Singh, Neeti Rajan; Steinberg, Frank; Roth, Thomas; Moline, Margaret; Harris, Stephen; Kapil, Ram P.

doi:10.1002/jcph.220

Cited by 89 publications

(68 citation statements)

References 35 publications

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“…Such similarity in drug exposure of zolpidem had also been reported for the marketed sublingual zolpidem lozenge (Intermezzo) in which the gender difference resulted in gender-specific dose levels for females (1.75 mg) and males (3.5 mg) for safety reason (for example, next-morning residual effect) as recommended by U.S. FDA. 14,15 Similar to the historical clinical data of Intermezzo, [13][14][15] our results of weight-normalized clearance also indicated that male subjects cleared zolpidem from body at a higher rate than female subjects, which warrant further investigation in the following clinical studies.…”

supporting

confidence: 78%

“…11,13 Since the clearance rate of zolpidem in women is lower than that in men, the dose for Intermezzo recommended by US FDA is 1.75 mg for women and 3.5 mg for men, which is taken only once per night. 11,14,15 The starting dose of ZNS in this dose-escalating clinical study was selected to be 1.75 mg/day since this dose should be safe in humans, based on our non-clinical PK and toxicological studies in dogs and previous human experience at similar or higher dose of zolpidem tartrate administered by oral or intravenous routes. In an acute toxicity and toxicokinetic study, 3 groups of sleep deprived rats received IN doses of ZNS (0.208 mg/rat, 0.416 mg/rat, or 0.832 mg/rat) once daily for 7 consecutive days.…”

Section: Brief Summarymentioning

confidence: 99%

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

Wang³

et al. 2016

Journal of Clinical Sleep Medicine

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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.

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confidence: 78%

Section: Brief Summarymentioning

confidence: 99%

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

Wang³

et al. 2016

Journal of Clinical Sleep Medicine

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“…1,2 The peak concentration of the sublingual formulation of zolpidem was 45% higher in women than men. 3 Some studies have shown that these pharmacokinetic differences are associated with safety differences. At 5 h post daytime zolpidem administration and testing, poorer automobile driving was found 3 and in the morning 4 h after middle of the night zolpidem administration, poorer automobile driving was shown in women than men.…”

Section: Introductionmentioning

confidence: 99%

Gender Differences in the Efficacy and Safety of Chronic Nightly Zolpidem

Roehrs

Roth

2016

Journal of Clinical Sleep Medicine

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Study Objectives: Studies have shown pharmacokinetic differences for hypnotics in women compared to men, but few studies have assessed either shortor long-term differences in efficacy and safety. Methods: To evaluate gender differences in the efficacy and safety of chronic nightly zolpidem (10 mg), we did a post hoc assessment of a large clinical trial. In the trial, participants with primary insomnia (n = 89), ages 23-70, meeting DSM-IV-TR criteria for primary insomnia were randomized, double blind, to nightly zolpidem, 10 mg (n = 47) or placebo (n = 42) 30 minutes before bedtime nightly for 12 months. Polysomnographic sleep on 2 nights in months 1 and 8 and likelihood of next-day sleepiness, rebound insomnia, and dose escalation were evaluated in months 1, 4, and 12. Results: Relative to placebo, zolpidem significantly increased sleep efficiency and reduced sleep latency and wake after sleep onset assessed at months 1 and 8, with no differences in efficacy between women and men and no diminution of efficacy over months. On a next-day multiple sleep latency test (MSLT), no residual sedation was observed for either women or men. No rebound insomnia or dose escalation was seen with no gender differences in either. Conclusions:In adults with primary insomnia, nightly zolpidem administration showed no gender differences in acute or chronic efficacy or in next-day sleepiness. Zolpidem remained efficacious and safe across 12 months. Clincial Trials Registration: ClinicalTrials.gov Identifier: NCT01006525; Trial Name: Safety and Efficacy of Chronic Hypnotic Use; http://clinicaltrials.gov/ct2/ show/NCT01006525. Keywords: gender differences, primary insomnia, zolpidem Citation: Roehrs TA, Roth T. Gender differences in the efficacy and safety of chronic nightly zolpidem. J Clin Sleep Med 2016;12(3):319-325. I NTRO DUCTI O NGender-related pharmacokinetic differences in zolpidem plasma concentration have been reported, with plasma concentrations in women being higher and clearance slower than in men. Men metabolized the 10 mg standard formulation of zolpidem at approximately double the rate of women.1,2 The peak concentration of the sublingual formulation of zolpidem was 45% higher in women than men.3 Some studies have shown that these pharmacokinetic differences are associated with safety differences. At 5 h post daytime zolpidem administration and testing, poorer automobile driving was found 3 and in the morning 4 h after middle of the night zolpidem administration, poorer automobile driving was shown in women than men. 4 It should be noted that these pharmacokinetic studies were done in healthy volunteers and not patients with insomnia for whom this medication is indicated.Many insomnia patients use prescription hypnotics chronically, with over half taking hypnotics longer than 4 weeks, likely due to their chronic and frequent symptomatology. [5][6][7][8] Given this evidence of long-term hypnotic use in insomnia, it is also of interest to assess long-term gender differences in the efficacy and safety of zolpidem. Contro...

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“…Surprisingly, experimental studies of sex differences in the pharmacokinetics and pharmacodynamics of zolpidem in human men and women found that body weight, not sex, is the culprit. Women clear zolpidem from their system more slowly than men, but body weight eliminates the statistical significance of sex as a variable in clearance of zolpidem (8). Because body weight, not sex, is the independent biological variable, sex-based preclinical research protocols would likely not have predicted sex differences in rates of ADE with zolpidem.…”

mentioning

confidence: 99%

Focus on preclinical sex differences will not address women’s and men’s health disparities

Richardson

Reiches

Shattuck‐Heidorn

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Last spring, the US National Institutes of Health (NIH) announced a new policy calling for the use of both male and female materials-animals, tissues, cells, and cell lines-in preclinical research (1). Canada and the European Union have recently instituted similar policies. Advocates argue that requiring analysis of sex in preclinical research will advance scientific understanding of sex differences in human health outcomes, such as higher rates of adverse drug events (ADE) in women compared with men (2). We disagree.To be useful in addressing health disparities, sex-linked variables in preclinical materials must effectively model differences between human men and women. In the absence of evidence that this is so, the addition of sex as a variable in all preclinical studies is likely to introduce conceptual and empirical errors into research. Biomedical research institutions and funders can better remedy sex differences in health outcomes by focusing on the scientific study of the interaction of sex and gender variables in health outcomes in human populations.Sex differences in rates of ADE may be a result of biological factors, gender-related social factors, or a combination of sex-and gender-related variables. "Sex" refers to chromosomal complement, reproductive organs, or specific hormones related to sexual reproduction. "Gender" refers to sociocultural norms, expectations, and practices ascribed to males and females (3). Gendered factors, such as women's propensity to take multiple pharmaceuticals simultaneously (polypharmacy) compared with men, and their greater likelihood to see medical doctors than men, play a well-documented role in sex differences in health outcomes (4-6).Take the case of zolpidem (Ambien). In 2013, the Food and Drug Administration issued an unprecedented advisory reducing the recommended zolpidem dosage for women, following reports of higher numbers of ADE in women compared to men (7). Since then, researchers have sought the biological basis for this sex difference in reports of zolpidem-related ADE. Surprisingly, experimental studies of sex differences in the pharmacokinetics and pharmacodynamics of zolpidem in human men and women found that body weight, not sex, is the culprit. Women clear zolpidem from their system more slowly than men, but body weight eliminates the statistical significance of sex as a variable in clearance of zolpidem (8). Because body weight, not sex, is the independent biological variable, sex-based preclinical research protocols would likely not have predicted sex differences in rates of ADE with zolpidem.The zolpidem case provides an example of the need for studies aimed at uncovering the embodied interaction of human sex-and gender-related variables in sex differences in ADE. Weight is distributed differentially across male and female bodies. In presentday American populations, weight may interact with gender-related variables. For example, higher rates of zolpidem use and polypharmacy in women compared to men, as well as biopsychosocial factors, such as wome...

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Gender differences in pharmacokinetics and pharmacodynamics of zolpidem following sublingual administration

Cited by 89 publications

References 35 publications

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

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

Gender Differences in the Efficacy and Safety of Chronic Nightly Zolpidem

Focus on preclinical sex differences will not address women’s and men’s health disparities

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