Drugs Aging (2014) 31:731–736
DOI 10.1007/s40266-014-0211-3
SHORT COMMUNICATION
Pharmacokinetics of Zolpidem from Sublingual Zolpidem
Tartrate Tablets In Healthy Elderly Versus Non-Elderly Subjects
David J. Greenblatt • Jerold S. Harmatz •
Nikhilesh N. Singh • Frank Steinberg •
Thomas Roth • Stephen C. Harris • Ram P. Kapil
Published online: 23 September 2014
Ó Springer International Publishing Switzerland 2014
Abstract
Background Pharmacokinetic parameters of sedative–
hypnotic medications can be influenced by age and gender.
Objective This study analyzed pharmacokinetic parame-
ters of zolpidem, formulated as a sublingual zolpidem
tartrate tablet (ZST; IntermezzoÒ), in healthy elderly
males and females (mean age 72 years) and in non-elderly
males and females (34 years).
Methods This was a randomized, single-dose, open-label,
two-way crossover study evaluating pharmacokinetic
parameters of 1.75 and 3.5 mg dosages of ZST in elderly
subjects (n = 22), and 3.5 mg dosages of ZST in non-
elderly subjects (n = 24). Main outcome measures were
pharmacokinetic parameters, including area under the
plasma concentration–time curve (AUC), maximum
observed concentration (Cmax), time to reach Cmax (Tmax),
elimination half-life (T‘), and apparent oral clearance
(CL/F).
D. J. Greenblatt (&)
J. S. Harmatz
Department of Integrative Physiology and Pathobiology, Tufts
University School of Medicine, 136 Harrison Avenue, Boston,
MA 02111, USA
e-mail: dj.greenblatt@tufts.edu
N. N. Singh
F. Steinberg
Transcept Pharmaceuticals, Inc., Point Richmond, CA, USA
T. Roth
Sleep Disorders and Research Center, Henry Ford Hospital,
Detroit, MI, USA
S. C. Harris
R. P. Kapil
Purdue Pharma LP, Stamford, CT, USA
Results Dose proportionality in zolpidem exposure was
maintained between 1.75 and 3.5 mg doses for both
elderly females and males. With administration of the
3.5 mg dose of ZST to elderly and non-elderly subjects,
significantly higher systemic exposure was seen in
elderly females (Cmax ?44.6 %, P \ 0.01; AUC
?40.4 %) compared with non-elderly females. However,
systemic exposure was only modestly higher in elderly
males compared with non-elderly males. Greater expo-
sure was seen in elderly females compared to males
(Cmax ?46.8 %, P \ 0.01; AUC ?31.4 %). In this study,
exposure between non-elderly females and males was
equivalent. Changes in T‘ and Tmax values were not
observed, with no significant age effect on oral clear-
ance. There were no apparent differences in tolerability
among age and gender groups.
Conclusion Elderly individuals were found to have
higher Cmax and AUC values compared with non-elderly
subjects. Cmax and AUC were greater in elderly women
compared with elderly men.
Key Points
Dose proportionality in zolpidem exposure was
maintained between 1.75 and 3.5 mg doses for both
elderly females and males, which had previously
been shown for higher doses.
Elderly females had higher exposures to zolpidem
than non-elderly females.
Elderly individuals receiving sublingual zolpidem
were found to have higher Cmax and AUC values
compared with non-elderly.
732
1 Introduction
Insomnia and several other sleep disorders occur with
disproportionate prevalence among the elderly, and as such
hypnotic medications are commonly used by elderly indi-
viduals [1–6]. Extensive research data on hypnotic drug
disposition and effects in the elderly population indicates
that older persons may have reduced metabolic clearance
of hypnotic medications (leading to higher plasma con-
centrations), increased intrinsic sensitivity to hypnotic
drugs, or both [7–9]. For these reasons, recommended
doses of sleep-inducing medications for the elderly are
generally lower than for non-elderly adults.
The imidazopyridine derivative zolpidem is extensively
used as a hypnotic medication throughout the world [10,
11]. Retail prescriptions for zolpidem in the USA exceeded
30 million in calendar year 2009 [12]. Two clinical studies
have demonstrated that clearance of zolpidem in healthy
elderly individuals is significantly lower than in non-
elderly adults of comparable body size [13, 14]. Approved
dosage recommendations accordingly mandate that initial
doses of zolpidem taken at bedtime by older persons should
be 50 % of what is usually prescribed for younger indi-
viduals. Zolpidem clearance is also reported to be lower in
women than in men [13–17], leading to similar recom-
mendations for reduced dosage in women.
A low-dose buffered sublingual zolpidem tartrate tablet
(ZST) formulation (IntermezzoÒ) [18–22] has been
approved for clinical use in the treatment of patients with
difficulty returning to sleep after a middle-of-the-night
awakening—an insomnia variant that is common in the
elderly [23–25]. As with other zolpidem formulations used
in clinical practice, lower doses of ZST are recommended
for the elderly. The present study evaluated the effect of
age, gender, and dose on the pharmacokinetics of zolpidem
administered as ZST.
2 Methods
2.1 Overall Design
This was a randomized, single-dose, open-label, two-way
crossover study evaluating pharmacokinetic parameters for
1.75 and 3.5 mg dosages of ZST (Purdue Pharma LP,
Stamford, CT, USA) in healthy, non-smoking elderly
subjects, and a single dose of 3.5 mg ZST in healthy, non-
smoking non-elderly subjects. Subjects were excluded if
they had any clinically significant ongoing medical con-
dition, including other sleep disorders, which might jeop-
ardize their safety or interfere with the absorption,
distribution, metabolism, or excretion of the drug, or if any
drugs (or herbal preparations) known to inhibit or induce
D. J. Greenblatt et al.
activity hepatic cytochrome P450 isoenzymes (CYP) 3A4,
2D6 or 1A2 were used within 30 days prior to screening.
The study was conducted at a single study centre (Com-
munity Research Management Associates, Inc., Cincinnati,
OH, USA).
2.2 Subjects
A total of 48 healthy subjects were enrolled in the study: 24
elderly (8 males and 16 females), with mean age (standard
deviation [SD]) of 72 ± 5 years; and 24 non-elderly (15
males and 9 females), mean age of 35 ± 9 years. Twenty-
two of the elderly and all of the non-elderly subjects
completed the study.
Based on within-group variability in zolpidem pharma-
cokinetic parameters observed in prior studies [14–17],
power calculations indicated that the samples sizes were
sufficient to detect a 35 % difference between groups in
principal pharmacokinetic parameters, with alpha = 0.05
and power of at least 0.80.
2.3 Treatment
Prior to the start of ZST administration, the elderly subjects
were randomized to the order of 1.75 and 3.5 mg ZST
dosages. Elderly subjects were then given a single sublin-
gual dose of either 1.75 or 3.5 mg ZST, with treatments
separated by a washout period of 5 ± 2 days. Subjects in
the non-elderly group were given a single 3.5 mg dose of
ZST. All subjects underwent a supervised overnight fast of
at least 10 h prior to dosing. Subjects were dosed with ZST
between 0700–0800 h, and subsequently fasted for a period
of 4 h.
2.4 Pharmacokinetic Measurements
After administration of ZST, blood samples were drawn
at multiple time points, with the duration of sampling
(12 h) sufficient to allow determination of the total area
under the plasma concentration–time curve. Plasma con-
centrations of zolpidem free base were determined by
liquid chromatography–mass spectroscopy, as described
previously [16].
Pharmacokinetic parameters were determined by model-
independent (non-compartmental) methods [14–17].
Parameters measured included: area under the plasma
concentration–time curve (AUC) from time zero to infinity
(AUC0–inf), and from time zero to the last measurable
concentration (AUC0–t); the maximum measured plasma
concentration (Cmax); time of observed Cmax (Tmax); elim-
ination half-life (T‘); and apparent oral clearance with and
without normalization for body weight (CL/F) for the 1.75
and 3.5 mg doses of ZST. Descriptive statistics were
Sublingual Zolpidem Kinetics: Age and Gender Effects
generated for demographic and pharmacokinetic variables
for all subjects, and for men and women separately.
2.5 Statistical Methods
The effects of age, gender, and dosage on pharmacokinetic
parameters of zolpidem were evaluated by Student’s t test.
Effects of dosage (1.75 mg versus 3.5 mg) within the
groups of elderly subjects who received both doses on two
occasions were evaluated using Student’s paired t test. For
comparisons of independent groups (non-elderly versus
elderly, or male versus female), Student’s independent
t test was used.
3 Results
Aside from age, other demographic characteristics were
generally comparable between the elderly and non-elderly
groups. Female weight and height were characteristically
lower compared with males in both groups (Table 1).
There was a higher percentage of female subjects in the
elderly cohort.
Among elderly subjects, pharmacokinetic parameters for
zolpidem were linear and were dose-independent for both
male and female subject groups (Table 2). Cmax, AUC0–t,
and AUC0–inf proportional to dose, while Tmax, T‘ and
CL/F—with and without normalization for body weight—
were nearly identical between the 1.75 and 3.5 mg doses.
Among subjects receiving the 3.5 mg dosage of ZST,
elderly subjects had higher plasma concentrations than
non-elderly individuals within the same gender group
(Fig. 1; Table 2). The age effect was more pronounced
among female subjects. Zolpidem Cmax was significantly
higher in elderly than in non-elderly women (94 versus
65 ng/mL, P \ 0.003). CL/F was lower in elderly than in
non-elderly women, with the difference approaching sig-
nificance (154 versus 225 mL/min, P = 0.08). Among
men, differences between non-elderly and elderly groups
were not significant.
Gender effects on zolpidem kinetics were evident in the
elderly subject group. At both the 1.75 and 3.5 mg ZST
Table 1 Characteristics of study participants (pharmacokinetic population)
Characteristic Non-elderly subjects
Males [n = 15]
Age [years; mean (SD)] 31 (8)
Weight [kg; mean (SD)] 92 (10)
Height [cm; mean (SD)] 180 (19)
BMI [kg/m2; mean (SD)] 29 (8)
BMI body mass index, SD standard deviation
733
doses, zolpidem Cmax was significantly higher among
female subjects (Table 2; Figs. 1, 2). AUC values were
higher and clearance values lower in women than in men,
although only the AUC0–t difference at the 1.75 mg dosage
approached significance (P = 0.093). Gender effects were
not evident in the non-elderly subject group.
4 Discussion
The effect of age on the pharmacokinetics of orally
administered zolpidem tablets (not ZST) was evaluated in
two previous studies [13, 14]. In one of those studies,
zolpidem AUC averaged 1.7 times higher in healthy elderly
subjects compared to young adults receiving the same dose
[13]. However, the data were not reported by gender in that
report. In another study of standard immediate-release oral
zolpidem tablets, mean zolpidem AUC was 3.6 times
higher in elderly compared to young adult male subjects
[14]. Among female participants, the corresponding AUC
factor, comparing elderly and young women, was 1.6.
The present study evaluated the profile of zolpidem
pharmacokinetics following administration of ZST to
healthy elderly and non-elderly volunteers. In contrast to
previous reports, there were minimal differences between
non-elderly and elderly male subjects in any of the phar-
macokinetic parameters for zolpidem. Among female
subjects, zolpidem Cmax was significantly higher in elderly
than in non-elderly women. AUC was also higher in the
elderly females, but the difference was not significant.
Inconsistencies among studies of age effects on zolpidem
kinetics are probably explained by intrinsic variations in
metabolic capacity among different subject groups studied
under different conditions. In any case, lower metabolic
clearance and increased pharmacodynamic sensitivity to a
number of sedative–hypnotic medications have been
reported for elderly individuals [7–9]. Approved product
labelling for all zolpidem dosage forms mandates the use of
lower starting doses for elderly patients compared to non-
elderly adults.
Five previous studies have demonstrated higher AUC
values and lower clearance values among healthy young
Elderly subjects
Females [n = 9] Males [n = 8] Females [n = 14]
41 (6) 72 (6) 72 (4)
73 (11) 85 (12) 72 (15)
169 (3) 175 (8) 160 (7)
26 (3) 28 (3) 28 (4)
734 D. J. Greenblatt et al.

Table 2 Summary of pharmacokinetic variables

Parameter* Elderly subjects [ZST 1.75 mg] Elderly subjects [ZST 3.5 mg] Non-elderly subjects [ZST 3.5 mg]
Males [n = 8] Females [n = 14] Males [n = 8] Females [n = 14] Males [n = 15] Females [n = 9]

Cmax [ng/mL] 31 (4.4)c 47 (3.8)c 64 (7.8)b 94 (5.4)a,b 60 (3.5) 65 (6.4)a

Tmax [h] 0.46 (0.25–1.55) 0.42 (0.17–1.57) 0.54 (0.25–2.0) 0.46 (0.17–0.83) 0.67 (0.43–2.0) 0.67 (0.42–1.0)
T‘ [h] 2.9 (0.3) 2.7 (0.3) 2.8 (0.3) 2.7 (0.3) 2.8 (0.2) 2.3 (0.3)
AUC0–t [ng
h/mL] 129 (21) 185 (21) 267 (49) 351 (41) 238 (22) 250 (44)
AUC0–inf [ng
h/mL] 142 (25) 204 (25) 291 (59) 388 (52) 260 (27) 268 (51)
CL/F [mL/min] 206 (39) 142 (19) 212 (44) 154 (21) 206 (20) 225 (36)
CL/F [mL/min/kg] 2.56 (0.60) 2.12 (0.30) 2.66 (0.70) 2.31 (0.35) 2.28 (0.25) 3.25 (0.62)
AUC area under the plasma concentration–time curve, AUC0–inf AUC from time zero to infinity, AUC0–t AUC from time zero the last mea-
surable plasma concentration, CL/F apparent oral clearance, Cmax maximum observed concentration, SD standard deviation, T‘ elimination
half-life, Tmax time to reach Cmax, ZST sublingual zolpidem tablet
*Values are reported as mean (±SD); Tmax is reported as median (minimum, maximum)
Comparisons via Student’s independent t test:
a
P \ 0.01 (non-elderly versus elderly female, 3.5 mg ZST)
b
P \ 0.01 (elderly male versus elderly female, 3.5 mg ZST)
c
P \ 0.02 (elderly male versus elderly female, 1.75 mg ZST)

90 90
MALE SUBJECTS FEMALE SUBJECTS
PLASMA ZOLPIDEM (ng/mL)

PLASMA ZOLPIDEM (ng/mL)

80 80
Non-elderly Non-elderly
Elderly 70 Elderly
70

60 60

50 50

40 40

30 30
20
20
10
10
0
0

0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8
HOURS HOURS

Fig. 1 Mean (± standard error) plasma zolpidem concentrations for the first 8 h after a 3.5 mg dose of zolpidem administered as sublingual
zolpidem tablets (ZST) to healthy elderly and non-elderly male (left) and female (right) volunteers

female subjects receiving single doses of zolpidem com-
pared to young males receiving the same dose [13–17]. The
gender differences are observed whether zolpidem is
administered intravenously, as a standard oral tablet, or as
ZST. The mechanism of the gender difference is not
established. Clearance of zolpidem is dependent on several
CYP enzymes, with CYP3A isoforms accounting for about
60 % of clearance based on in vitro studies [26]. In con-
trast, for the majority of other drugs that are biotrans-
formed largely or entirely by CYP3A isoforms, clearance
values are similar to or higher in non-elderly females
compared to males [9, 27].
Unlike previous reports, zolpidem AUC and clearance in
the present study were very similar between non-elderly
male and female subjects receiving the same dose of ZST.
Among elderly subjects, women had higher AUC and
lower clearance than men, but the difference was not sig-
nificant. The inconsistency among studies again is probably
explained by variations in the characteristics of study
populations studied under different conditions.
The clinical importance of gender-related differences in
zolpidem kinetics, as reported in a number of studies, is not
established. Specifically, we are not aware of any published
reports indicating that higher plasma concentrations of
zolpidem in women are associated with a greater preva-
lence of residual sedative or performance-impairing
effects, such as impaired driving ability the morning after
taking a bedtime dose of zolpidem [28]. The US Food and
Drug Administration has mandated that initial doses of
zolpidem be reduced by 50 % for non-elderly women, in
order to reduce the putative risk [29]. This is applicable for
all dosage forms of zolpidem—whether oral zolpidem
Sublingual Zolpidem Kinetics: Age and Gender Effects
50
ELDERLY SUBJECTS (1.75 mg dose)
PLASMA ZOLPIDEM (ng/mL)
40 Male
Female
30
20
10
0 Ltd, Cephalon, Inc., Cypress Pharmaceutical, Inc., Dove Pharmaceu-
0 1 2 3 4 5 6 7
HOURS
Fig. 2 Mean (± standard error) plasma zolpidem concentrations for
the first 8 h after a 1.75 mg dose of zolpidem administered as
sublingual zolpidem tablets (ZST) to elderly male or female subjects
tablets taken at bedtime, or ZST taken for middle-of-the-
night awakening. Further investigation is needed to estab-
lish whether this change in approved dosage results in an
improved risk–benefit balance [30].
5 Conclusion
Among non-elderly subjects receiving 3.5 mg ZST, gender
had only a small and non-significant effect on pharmaco-
kinetics. This contrasts with previous studies in which
young female subjects had higher Cmax and AUC than
young male subjects receiving the same dose [14–17].
Among the elderly volunteers, women had higher Cmax and
AUC than men. Within gender groups, the elderly had
higher Cmax and AUC than non-elderly subjects. However
these age and gender differences were not consistently of
statistical significance. The findings are compatible with
labelling recommendations requiring reduced doses of
zolpidem for women. However we are not aware of clinical
data indicating a risk of excessive sedation among women.
Acknowledgments Funding for this study was provided by Trans-
cept Pharmaceuticals, Inc. The authors received editorial/writing
support in the preparation of this manuscript, funded by Purdue
Pharma LP. Gautam Bijur, PhD, and a team from Excerpta Medica,
and Margaret Moline, PhD, and Margi Goldstein, PhD, who are
employees of Purdue Pharma LP, provided editorial and writing
assistance. The authors are fully responsible for all content, editorial
decisions and opinions expressed in this study.
Conflict of Interest Statement Dr Greenblatt has served as a sci-
entific advisor to Transcept Pharmaceuticals, Inc., and Somnus
Therapeutics, Inc.
Mr Harmatz has no potential conflicts of interest to declare.
Dr Singh is employed by Transcept Pharmaceuticals, Inc.
Dr Steinberg is a consultant to Transcept Pharmaceuticals, Inc.
Dr Roth has received grants/research support from: Apnex
735
Medical, Inc., Aventis Pharmaceuticals, Inc., Cephalon, Inc., Glaxo-
SmithKline plc, Merck & Co., Inc., Neurocrine Biosciences, Inc.,
Pfizer, Inc., Sanofi US, Schering-Plough Corp., Sepracor, Inc.,
Somaxon Pharmaceuticals, Inc., Somnus Therapeutics, Inc., Syrex
Corp., Takeda Pharmaceutical Co., Ltd, Transcept Pharmaceuticals,
Inc., Ventus Medical, Inc., Wyeth, LLC, and Xenoport, Inc. He has
also acted as a consultant for Abbott Laboratories, Acadia Pharma-
ceuticals, Inc., Acologix, Inc., Acorda Therapeutics, Inc., Actelion
Pharmaceuticals Ltd, Addrenex Pharmaceuticals, Inc., Alza Corp.,
Alkermes, Ancile, Ansell Ltd., Arena Pharmaceuticals, Inc., Astra-
Zeneca plc, Aventis Pharmaceuticals, Inc., Aver Pharmaceuticals Pvt.
Ltd, Bayer AG, Bristol-Myers Squibb Company, BTG International
ticals, Eisai Co., Ltd, Elan Corp., Eli Lilly and Company, Evotec AG,
8 Forest Laboratories, Inc., GlaxoSmithKline plc, Hypnion, Inc., Impax
Laboratories, Inc., Intec Pharma Ltd, Intra-Cellular Therapies, Inc.,
Jazz Pharmaceuticals plc, Johnson & Johnson, Inc., King Pharma-
ceuticals, Inc., Lundbeck A/S, McNeil Consumer Healthcare, Medic-
iNova, Inc., Merck & Co., Inc., Neurim Pharmaceuticals Ltd,
Neurocrine Biosciences, Inc., Neurogen Corp., NovaDel Pharma,
Inc., Novartis AG, Ocera Therapeutics, Inc., Orexo AB, Organon
Pharmaceuticals, Inc., Otsuka Pharmaceutical Co., Ltd, Prestwick
Pharmaceuticals, Inc., Procter & Gamble, Pfizer, Inc., Purdue Pharma
LP, Teva, Hoffman-La Roche, Inc., Sanofi SA, Schering-Plough
Corp., Sepracor, Inc., Servier, Shire plc, Somaxon Pharmaceuticals,
Inc., Syrex Corp., Takeda Pharmaceutical Co., Ltd, Transcept
Pharmaceuticals, Inc., Vanda Pharmaceuticals, Inc., Ventus Medical,
Inc., VivoMetrics, Inc., Wyeth, LLC, Yamanuchi Pharmaceutical Co.,
Ltd, and Xenoport, Inc. In the last 12 months, he has participated in
speaking engagements supported by Purdue Pharma LP and has
served as a speaker sponsored by Cephalon, Sanofi and Takeda.
Dr Harris is employed by Purdue Pharma LP.
Dr Kapil is employed by Purdue Pharma LP.
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