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Volume 12 No. 11
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Scientific Investigations

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

Cheng-Tai Li, MD, PhD1; Tung-Ping Su, MD, PhD1; Yanfeng Wang, PhD2; Benjamin Lee, PharmD2; Melvin Toh, MD2; Tony Ho, PhD2
1Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan; 2Renascence Therapeutics Limited, New Territories, Hong Kong

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 Tmax of 0.42, 0.76 and 0.50 h, respectively, followed by rapid decreases at all three doses. Cmax, AUC0-t, and AUC0-∞ were found to increase in a dose-proportional manner. Female subjects had generally higher AUC0-t, AUC0-∞, 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.

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. J Clin Sleep Med 2016;12(11):1453–1459.


INTRODUCTION

Insomnia is characterized by difficulties in sleep initiation, sleep maintenance, or poor sleep quality, resulting in daytime functioning impairment. In the United States of America (USA) and Europe, about 10% of adults suffer from chronic insomnia (dissatisfaction with the quantity, quality or timing of sleep for a period of at least one month) while 30% to 40% complain of transient insomnia (lasting for a few days to a couple of weeks).13 In Taiwan, a study examining the prevalence rate of insomnia found that over 25% of Taiwanese adults experienced insomnia.4 In Hong Kong, 39.4% of the adult population (equivalent to 2.2 million) are affected by insomnia.5 It is recognized that, left untreated, transient insomnia can evolve to a chronic condition.13 Indeed, individuals reporting disturbed sleep are more likely to report recurrent health problems and emotional distress.6

To date, pharmacotherapy is the most commonly used treatment strategy for subjects with insomnia.7 Zolpidem, a nonbenzodiazepine agent, is one of the most frequently prescribed hypnotic drugs. Its tartrate salt is an imidazopyridine with strong sedative actions, but only minor anxiolytic, muscle relaxant, or anticonvulsant properties are found. Zolpidem has a rapid onset and short duration of hypnotic action and at usual doses decreases time to sleep onset and increases duration of sleep with little apparent effect on sleep stages.810 It is rapidly absorbed from the gastrointestinal tract after oral doses with peak plasma concentrations being reached within 3 hours, followed by first-pass metabolism. Previous studies have reported that its absolute bioavailability is about 70%, with an elimination half-life of about 2.5 hours.10,11

BRIEF SUMMARY

Current Knowledge/Study Rationale: In order to provide an alternative and effective approach for administering zolpidem other than the conventional oral dosage form, an intranasal formulation, zolpidem nasal spray (ZNS), is developed and evaluated in healthy volunteers. Our preliminary animal studies in rats and dogs indicated that the nasal absorption of zolpidem tartrate was rapid and efficient, with significantly higher drug concentration and faster absorption in animal plasma as well as good local tolerability in terms of minimal nasal irritation; if successfully developed, this novel nasal formulation can become a unique medication suitable for as-needed or intermittent use in subjects with sleep initiation difficulty and middle-of-the-night awakening.

Study Impact: This is the first study that evaluates the pharmacokinetic parameters of a novel zolpidem nasal spray in healthy volunteers. Our results indicate that zolpidem was rapidly absorbed and eliminated after intranasal administration of ZNS, with dose proportionality found at the evaluated range of doses; intranasal exposure of zolpidem was generally higher in female subjects than that in male subjects, and ZNS is safe, well tolerated, and warranted for further clinical development.

Generally, zolpidem tartrate is administered as oral tablets under the trade name of Ambien or Stilnox, and is available as a standard immediate release tablets (5 mg and 10 mg), or as a controlled release tablet (6.25 mg and 12.5 mg).10 Both of these marketed formulations recommend that patients take the medication only once per night immediately before bedtime in anticipation of insomnia, with at least 7 to 8 hours remaining before the planned time of awakening to avoid potential next-day effects. Among the generic versions of zolpidem tartrate approved by the U.S. Food and Drug Administration (FDA), several alternative dosage forms with different routes of administration can be found in the market, for example, buccal/ sublingual tablet (Edluar), and oral spray (ZolpiMist).9,12 A sublingual zolpidem tablet called Intermezzo was approved by US FDA for the indication of middle-of-the-night awakening (MOTN).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. No abnormality was found in body weights, food consumption, hematology, clinical chemistry, urinalysis, organ weights/ratios, and gross pathology observations. Because of the technical feasibility (limitation of spray volume and concentration), the no observed adverse effect level (NOAEL) was established to be 0.832 mg/rat for IN administration. This dose (0.832 mg/rat) is equivalent to a human IN dose of 32.2 mg/ subject based on body surface area. This available information suggests that the present study using 1.75 to 5 mg of zolpidem has a favorable potential risk-benefit ratio.

In comparison to the conventional oral dosage form, intra-nasal formulation can offer several advantages such as rapid absorption, fast onset of action, high bioavailability, and ease of use. Therefore, the rationale for the development of the product, zolpidem nasal spray (ZNS), is to provide an alternative and effective approach for administering zolpidem. Our preliminary studies in rats and dogs indicated that the nasal absorption of zolpidem tartrate is rapid and efficient, with significantly higher drug concentration and faster absorption in animal plasma as well as good local tolerability (minimal nasal irritation). If successfully developed, this novel ZNS nasal formulation will provide a unique and alternative medication approach suitable for as-needed or intermittent use for subjects with sleep initiation difficulty and middle-of-the-night awakening.

METHODS

Subject Selection

This study was conducted in Taipei Veterans General Hospital at No. 201, Sec. 2, Shipai Road, Beitou District, Taipei 112, Taiwan, from November 23, 2012 to May 03, 2013. The study protocol was approved by the institutional review board (IRB) of Taipei Veterans General Hospital on June 15, 2012. This study was conducted with informed consent obtained according to the ethical principles stated in the latest version of the Declaration of Helsinki, the applicable guidelines for Good Clinical Practice, or the applicable laws and regulations of Department of Health in Taiwan. Twenty-four male and 22 female volunteers (total 46) were recruited through advertisements in local media posted by the contract research organization in Taiwan (QPS-Qualitix Clinical Research Co., Ltd.) for initial screening. All enrolled subjects were provided with information regarding the study drug product and the procedures and potential risks involved in participating in the study prior to entering the study. Before each subject was admitted to the study, informed consent was obtained from the subject according to the regulatory and legal requirements. The study population consisted of healthy subjects who had provided written consent and met all inclusion criteria and none of the exclusion criteria. The inclusion criteria for the study included: (1) healthy males or females between the ages of 20–64 years; (2) body mass index (BMI) of 18 to 30 kg/m2 and a total body weight > 45 kg (99 lbs); (3) accessible vein for blood sampling; (4) normal electrocardiogram (ECG) recording as per site's local practice; (5) no significant abnormalities in general physical examination as per site's local practice; (6) no abnormal findings in hematological and biochemical parameters as per site's local practice; (7) a signed and dated written informed consent from the subject; (8) ability to understand and willingness to comply with study procedures; (9) a negative serum pregnancy test within 1 day before the first dose of study drug for women of childbearing potential.

The subjects were excluded from entry if any of the criteria listed below were met at baseline: (1) females who were pregnant, breast-feeding or had positive pregnancy test; (2) history of treatments for alcoholism, substance abuse, or drug abuse within past 24 months; (3) evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or other significant disease or clinical findings at screening; (4) clinical significant rhinitis or rhinorrhea at screening; (5) insomnia, as defined by Diagnostic Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria, based on clinical interview; (6) history of hypersensitivity to zolpidem tartrate; (7) conditions upon screening which might contraindicate or require that caution be used in the administration of zolpidem tartrate; (8) inability to read and/or sign the consent form; (9) treatment with any other investigational drug during the 4 weeks prior to initial dosing for this study; (10) subjects who have donated blood within 4 weeks prior to initial dosing for this study; (11) lack of abstinence of at least 2 weeks for subjects who smoked or used tobacco products or were currently using nicotine products (patches, gums, etc.); (12) use of prescription or nonprescription drugs and dietary supplements within 7 days or 5 half-lives (whichever was longer) prior to dosing of study medication; (13) male and female subjects with reproductive potential who were not willing to use an allowed method of contraception.

Study Design

This was a single-dose, randomized, double-blind, sponsor-unblinded, placebo-controlled, dose escalating study to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ZNS in healthy male and female subjects. In each of the 3 cohorts (Cohort A–C), 12 subjects were randomly assigned to receive either an intranasal dose of ZNS (n = 10) or an intranasal placebo (n = 2), starting from the lowest dose (1.75 mg). Multiple venous blood samples (5 mL per sample) were collected at 0 (before dosing), 5, 10, 15, 20, 30, 45, 60, 90 minutes, and 2, 3, 4, 6, 8, 10, and 12 hours after dosing. Vital signs including blood pressure, heart rate, respiration rate, and body temperature were collected 30 minutes pre-dose, every hour during the first 3 hours after dosing, and then collected every 3 hours until discharge from the hospital. Frequency and type of clinical adverse effects (AEs), as well as results of clinical laboratory tests and nasal cavity examination were recorded during the study period.

Study Products and Administration

Each subject received only one dose of the study drugs, ZNS 1.75 mg, 3.5 mg, 5.0 mg, or placebo, on Study Day 1 via intranasal administration. The placebo intranasal spray was a vehicle spray with inactive ingredients consisting of the same ingredients as the ZNS formulation.

Determination of Plasma Zolpidem Concentration

Venous blood samples collected from the subjects were put into tubes containing sodium heparin (anticoagulant) at the aforementioned time points in the section of Study Design. After centrifugation at 3000 rpm for 10 min, the plasma samples were obtained and stored at −70°C until assay.

A validated liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was employed to determine the concentration of zolpidem in the human plasma samples collected during the study. Plasma samples were spiked with internal standards (IS; zolpidem-D6, 10 ng/mL, Cerilliant Corp., TX, USA), processed by protein precipitation extraction using acetonitrile, and analyzed using reverse-phase high performance liquid chromatography (HPLC) with Turbo Ion Spray MS/MS detection (Triple Quadrupole MS API-4000, Applied Biosystems, Inc.). The standard and QC solutions were separately prepared by dilution of zolpidem solution (Cerilliant Corp., TX, USA) with methanol. The separation of zolpidem was carried out using Luna Phenyl-Hexyl column (50 × 2.0 mm i.d., 5 μm, Phenomenex) at 4°C. The mobile phase was a mixture of water-to-formic acid (100:0.1, v/v) and acetonitrile-to-formic acid (100:0.1, v/v) pumped at a flow rate of 0.5 mL/min. Positive (M+H)+ ions for zolpidem and zolpidem-D6 were monitored in MRM mode. Analyte-to-IS peak area ratios for the standards were used to create a linear calibration curve using 1/χ2 weighted least-squares regression analysis. The lower limit of quantitation (LLOQ) is 0.5 ng/mL, and the calibration curve of zolpidem is linear over the concentration range of 0.5 to 200 ng/mL (r2 > 0.99).

The LC-MS/MS bioanalytical method had been validated with respect to linearity, sensitivity, accuracy, precision, dilution, selectivity, recovery, matrix effect, and injection carryover. Zolpidem stability in human plasma (anticoagulated by sodium heparin) was demonstrated for 6 freeze-and-thaw cycles at −70°C, 21 h at room temperature, and 155 days of long-term storage at −70°C.

Evaluation Criteria

Pharmacokinetic parameters for zolpidem measured in the plasma samples were calculated by non-compartmental methods using WinNonlin version 5.2 (Pharsight Inc, Cary, NC), which included area under the plasma concentration-time curve from 0 to the time of last quantifiable concentration (AUC0-t), area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC0-∞), maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), elimination constant rate (Kel), half-life (t1/2), and estimated total clearance rate (CL/F). Dose proportional linearity and gender effect on pharmacokinetics were also evaluated. Frequency and type of clinical adverse events (AEs), results of clinical evaluation including vital signs, ECG, nasal cavity examination and laboratory safety evaluations were conducted.

Statistical Analysis

Power regression model was used to assess gender effect on PK parameters. Analysis of dose proportionality for zolpidem was performed for the Cmax and AUC0-∞. One-way analysis of variance (ANOVA) was used to evaluate the statistical difference in geometric mean ratios of ln-transformed Cmax, AUC0-t and AUC0-∞ between male and female subjects with 95% confidence intervals, as well as the gender difference in mean values of Kel, t1/2, and CL/F. The Hodges-Lehmann method was employed to compare the median values of Tmax between male and female subjects.

RESULTS

Demographic characteristics of all 36 subjects studied in the 3 cohorts were summarized in Table 1, including the gender, age, height, weight, body mass index (BMI), and method of contraception. All the subjects aged in the range of 20 to 35 with BMI from 18.2 to 27.2.

Summary of demographic characteristics of study subjects (n = 36).

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Table 1

Summary of demographic characteristics of study subjects (n = 36).

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The mean zolpidem plasma concentration profiles in Cohorts A (1.75 mg), B (3.5 mg), and C (5.0 mg) are illustrated in Figure 1. No quantifiable concentrations of zolpidem were observed in pre-dose samples and in the placebo-treated subjects. The pharmacokinetic parameters of zolpidem following intranasal administration of ZNS at 3 different doses are summarized in Table 2. The peak plasma concentration (Cmax) of zolpidem was found at similar time range within 0.2 to 1.5 h (median 0.4 h) in Cohort A (ZNS 1.75 mg), 0.3 to 1.0 h (median 0.8 h) in Cohort B (ZNS 3.5 mg), and 0.2 to 1.0 h (median 0.5 hr) in Cohort C. The mean Cmax of zolpidem (38.6 ± 12.0 ng/mL, 55.6 ± 14.9 ng/mL and 98.2 ± 27.6 ng/mL in Cohort A, Cohort B, and Cohort C, respectively) showed proportional increase with the ZNS doses. Similarly, mean AUC0-t values of zolpidem (140 ± 75 ng·h/mL, 206 ± 75 ng·h/mL and 315 ± 126 ng·hr/mL) were elevated following the treatment with increasing doses of ZNS. Conversely, the mean terminal elimination half-lives (t1/2) of zolpidem were not prominently altered (2.6 ± 0.7 h, 2.4 ± 0.4 h, and 2.4 ± 0.5 h in Cohort A, Cohort B, and Cohort C, respectively). Similarly, the weight-normalized clearance of zolpidem was unchanged at the increasing doses of ZNS among all 3 cohorts (15408 ± 9002 mL/h/kg, 18464 ± 6647 mL/h/kg and 17870 ± 7651 mL/h/kg in Cohort A, Cohort B, and Cohort C, respectively).

Plasma concentration-time profiles of zolpidem after intranasal administration of ZNS in three cohorts of healthy subjects.

Mean (± SD) plasma concentration-time profiles of zolpidem after intranasal administration of ZNS in three cohorts of healthy subjects (n = 30). BQL were entered as zero concentrations of zolpidem and included as such in the calculation of mean values.

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Figure 1

Plasma concentration-time profiles of zolpidem after intranasal administration of ZNS in three cohorts of healthy subjects.

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Summary of pharmacokinetic parameters of zolpidem after 3 intranasal doses of ZNS.

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Table 2

Summary of pharmacokinetic parameters of zolpidem after 3 intranasal doses of ZNS.

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Dose proportionality was assessed using a power regression model based on the equation of log(y) = α + β*log(dose). As shown in Table 3, the geometric mean values of both Cmax (29.8 ng/mL, 51.1 ng/mL, and 82.1 ng/mL) and AUC0-∞ (83 ng·h/mL, 188 ng·h/mL, and 242 ng·h/mL) in the male subjects increased in a dose-proportion manner as reflected by the β values (0.95 and 1.04, respectively) which were near unity (although the 5 mg ZNS was slightly more than proportionally absorbed when compared to the lower doses). Similar results were obtained in the geometric means of Cmax (42.2 ng/mL, 58.2 ng/mL, and 110 ng/mL) and AUC0-∞ (176 ng·h/mL, 224 ng·h/mL, and 377 ng·h/mL) in the female subjects upon intranasal administration of ZNS at the dose of 1.75 mg (Cohort A), 3.5 mg (Cohort B), and 5.0 mg (Cohort C). In general, the β values were not significantly different from unity at the 5% level among the 3 cohorts, indicating that the values of both Cmax and AUC0-∞ increased in a dose-proportional manner with the escalating dose of ZNS in both male and female subjects.

Dose proportionality of pharmacokinetic parameters of zolpidem after three intranasal doses of ZNS.

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Table 3

Dose proportionality of pharmacokinetic parameters of zolpidem after three intranasal doses of ZNS.

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Mean plasma concentration-time profiles of zolpidem in male and female subjects were shown in Figure 2. The comparison of PK parameters between male and female subjects is tabulated in Table 4. The results indicated that Cmax and AUC0-∞ of zolpidem in female subjects were generally higher than those in male subjects following intranasal administration of ZNS at dose levels from 1.75 to 3.5 mg to 5.0 mg. As shown in Table 3, the geometric means of both Cmax and AUC0-∞ in the female subjects were also higher than those in the males. Therefore, the gender differences in Cmax and AUC0-∞ of zolpidem were evaluated using one-way ANOVA model. The ratio of geometric means of AUC0-∞ in male group to female group was 0.469 with 90% confidence limits (CI) of 0.258 to 0.853, following intranasal administration of ZNS at 1.75 mg. These results indicated that the drug exposure of zolpidem was significantly higher in female group than those in male group after intranasal administration of 1.75 mg in Cohort A.

Plasma concentration-time profiles of zolpidem after intranasal administration of ZNS in three cohorts of male and female healthy subjects.

Mean (± SD) plasma concentration-time profiles of zolpidem after intranasal administration of ZNS in three cohorts of male and female healthy subjects (n = 30). BQL were entered as zero concentrations of zolpidem and included as such in the calculation of mean values.

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Figure 2

Plasma concentration-time profiles of zolpidem after intranasal administration of ZNS in three cohorts of male and female healthy subjects.

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Gender effect of pharmacokinetic parameters of zolpidem after three intranasal doses of ZNS.

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Table 4

Gender effect of pharmacokinetic parameters of zolpidem after three intranasal doses of ZNS.

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The median difference of Tmax between the male and female subjects was −0.25 h with 95% CI of −1.27 to 0.00 h in Cohort A, indicating that Cmax in the male subjects was reached earlier when compared to that of the female subjects. Following intranasal administration of ZNS in the three cohorts, there were no significant differences in t1/2 between male and female subjects after receiving different intranasal dose of ZNS. On the contrary, the mean values of weight-normalized total clearance rate (CL/F) were approximately 118%, 16%, and 59% higher in male subjects than those in female subjects following intranasal administration of 3 ZNS doses, indicating that the male subjects cleared zolpidem from body at a higher rate than the female subjects (Table 4).

All 36 subjects were dosed as per protocol. Zolpidem nasal spray was generally well tolerated in the healthy subjects and the treatment emergent adverse events were summarized in Table 5. One subject experienced presyncope, one experienced syncope, 3 subjects had procedural dizziness while drawing pre-dose blood samples, and laboratory results of 2 subjects during follow-up assessment were recorded as adverse events. No serious adverse event was reported and no subject discontinued the study due to any adverse experience. No clinical significant findings were reported for laboratory values, physical examination, ECG and vital signs.

Summary of treatment emergent adverse events reported in the subjects (n = 30) after three intranasal doses of ZNS.

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Table 5

Summary of treatment emergent adverse events reported in the subjects (n = 30) after three intranasal doses of ZNS.

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DISCUSSION

The main objective of this study was to investigate the pharmacokinetics, safety and tolerability of ZNS at three different and escalating intranasal doses (1.75 mg, 3.5 mg, and 5.0 mg) administered in healthy volunteer subjects. A total number of 37 subjects were enrolled, and 36 subjects (19 male and 17 female subjects) completed the study.

Following intranasal administration of ZNS, zolpidem was found to be absorbed rapidly as indicated by the mean Tmax within 0.4 to 0.8 h, which is shorter than those of the conventional oral tablet of zolpidem (Ambien at 5 or 10 mg: Tmax = 1.6 h) and other marketed products (ZolpiMist at 5 or 10 mg: 0.9 h; Edluar at 10 mg: 1.4 h; Intermezzo at 1.75 or 3.5 mg: 0.6 to 1.3 h).11 The Cmax value of zolpidem could reach the therapeutic level at 20 ng/mL for all three tested doses of ZNS in both male and female subjects.10 The plasma concentration of zolpidem declined rapidly with mean t1/2 ranged from 2.4 to 2.6 h, which was kept unchanged. When dose proportionality was assessed among the three ZNS intranasal doses, there was no significant difference among β values (slope of power regression model). This suggests that ZNS exhibited linear pharmacokinetics over the dose from 1.75 mg to 3.5 mg to 5.0 mg in the tested healthy volunteers.

Regarding the gender difference of ZNS on the pharmacokinetics between male and female subjects, Cmax, AUC0-t and AUC0-∞ of zolpidem in female subjects were found to be generally higher than those in male subjects following intranasal administration of ZNS at dose levels at 1.75 mg, 3.5 mg and 5.0 mg (16% to 38% higher in female subjects for Cmax; 23% to 108% higher in females for AUC0-t; and 22% to 109% higher in females for AUC0-∞ than males). Although these analyses were conducted in 4 to 6 subjects in each group, the gender difference could still be observed on the pharmacokinetic parameters of zolpidem after intranasal dosing of ZNS. Meanwhile, as shown in Table 4, similar drug exposure of zolpidem was found in female subjects administered with 1.75 mg ZNS as compared to those in male subjects treated with 3.5 mg ZNS (AUC0-∞: 187 ng·h/mL vs. 198 ng·h/mL). 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,1315 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.

None of the enrolled subjects prematurely discontinued from the study due to adverse experiences. Most AEs were of mild intensity, indicating that ZNS was safe and generally well tolerated.

CONCLUSIONS

Zolpidem was rapidly absorbed and eliminated after intranasal administration of ZNS. Dose proportionality was found at the IN doses of ZNS ranged from 1.75 mg to 5.0 mg. Drug exposure of zolpidem was generally higher in female subjects than that in male subjects after intranasal administration of ZNS. ZNS was safe and well tolerated over the evaluated range of intranasal doses in this study.

DISCLOSURE STATEMENT

This trial was conducted at Taipei Veterans General Hospital and fully funded by Renascence Therapeutics Limited. Dr. Li is the attending psychiatrist of Taipei Veterans General Hospital and was appointed as the principle investigator of this study. Prof. Su was the Vice Superintendent of Taipei Veterans General Hospital and was appointed as the co-investigator of this study. Drs. Lee, Toh, Wang, and Ho were employees of Renascence Therapeutics Limited at the time of the study.

ABBREVIATIONS

AE

adverse event

ANOVA

analysis of variance

AUC0-t

area under curve from 0 to the time of last quantifiable concentration

AUC0-∞

area under curve from time zero extrapolated to infinity

BMI

body mass index

Cmax

maximum plasma concentration

CI

confidence interval

CL/F

estimated total clearance rate

DSM

Diagnostic and Statistical Manual of Mental Disorders

ECG

electrocardiogram

HPLC

high performance liquid chromatography

IN

intranasal

IRB

institutional review board

Kel

elimination constant rate

LC-MS/MS

liquid chromatography-tandem mass spectrometry

LLOQ

lower limit of quantitation

MOTN

middle-of-the-night awakening

NOAEL

no observed adverse effect level

PK

pharmacokinetics

t1/2

half-life

Tmax

time to reach maximum plasma concentration

ZNS

zolpidem nasal spray

ACKNOWLEDGMENTS

The authors thank the dedicated staff members of QPS–Qualitix Clinical Research Co., Ltd. for their expert technical assistance and management on this study. This study was financially supported by Renascence Therapeutics Limited.

REFERENCES

1 

Doghramji K, author. The epidemiology and diagnosis of insomnia. Am J Manag Care. 2006;12:S214–20. [PubMed]

2 

Leger D, Poursain B, authors. An international survey of insomnia: under-recognition and under-treatment of a polysymptomatic condition. Curr Med Res Opin. 2005;21:1785–92. [PubMed]

3 

Roth T, Drake C, authors. Evolution of insomnia: current status and future direction. Sleep Med. 2004;5:S23–30. [PubMed]

4 

Kao CC, Huang CJ, Wang MY, Tsai PS, authors. Insomnia: prevalence and its impact on excessive daytime sleepiness and psychological well-being in the adult Taiwanese population. Qual Life Res. 2008;17:1073–80. [PubMed]

5 

Wong WS, Fielding R, authors. Prevalence of insomnia among Chinese adults in Hong Kong: a population-based study. J Sleep Res. 2011;20:117–26. [PubMed]

6 

Bixler EO, Kales A, Soldatos CR, Kales jD, Healy S, authors. Prevalence of sleep disorders in the Los Angeles metropolitan area. Am J Psychiatry. 1979;136:1257–62. [PubMed]

7 

Kupfer DJ, Reynold CF 3rd, authors. Management of insomnia. N Eng J Med. 1997;336:341–6.

8 

Salva P, Costa J, authors. Clinical pharmacokinetics and pharmacodynamics of zolpidem: therapeutic implications. Clin Pharmacokinet. 1995;29:142–53. [PubMed]

9 

Greenblatt DJ, Roth T, authors. Zolpidem for insomnia. Expert Opin Pharmacother. 2012;13:879–93. [PubMed]

10 

Swainston Harrison T, Keating GM, authors. Zolpidem: a review of its use in the management of insomnia. CNS Drugs. 2005;19:65–89. [PubMed]

11 

Pergolizzi JV Jr, Taylor R Jr, Raffa RB, Nalamachu S, Chopra M, authors. Fast-acting sublingual zolpidem for middle-of-the-night wakefulness. Sleep Disord. 2014;2014:527109. [PubMed Central][PubMed]

12 

Neubauer DN, author. ZolpiMist: a new formulation of zolpidem tartrate for the short-term treatment of insomnia in the US. Nat Sci Sleep. 2010;2:79–84. [PubMed Central][PubMed]

13 

Greenblatt DJ, Harmatz JS, Roth T, Singh NN, Moline ML, Harris SC, Kapil RP, authors. Comparison of pharmacokinetic profiles of zolpidem buffered sublingual tablet and zolpidem oral immediate-release tablet: results from a single-center, single-dose, randomized, open-label crossover study in healthy adults. Clin Ther. 2013;35:604–11. [PubMed]

14 

Greenblatt DJ, Harmatz JS, Singh NN, et al., authors. Gender differences in pharmacokinetics and pharmacodynamics of zolpidem following sublingual administration. J Clin Pharmacol. 2014;54:282–90. [PubMed]

15 

Greenblatt DJ, Harmatz JS, von Moltke LL, et al., authors. Comparative kinetics and response to the benzodiazepine agonists triazolam and zolpidem: evaluation of sex-dependent differences. J Pharmacol Exp Ther. 2000;293:435–43. [PubMed]