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Vol. 293, Issue 2, 435-443, May 2000
Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine and New England Medical Center, Boston, Massachusetts (D.J.G., J.S.H., L.L.v.M., A.L.B.D., L.M.H.-J., R.I.S.); and Pharmacia and Upjohn Co., Kalamazoo, Michigan (C.E.W.)
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Abstract |
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 Top
 Abstract
 Introduction
Materials and Methods
Results
Discussion
References
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Eighteen healthy volunteers (10 men and 8 women) participated in a
single-dose, double-blind, three-way crossover pharmacokinetic and
pharmacodynamic study. Treatment conditions were 0.25 mg of triazolam,
a full-agonist benzodiazepine ligand; 10 mg of zolpidem, an
imidazopyridine having relative selectivity for the type 1 benzodiazepine receptor subtype; and placebo. Weight-normalized clearance of triazolam was higher in women than in men (8.7 versus 5.5 ml/min/kg), but the difference was not significant. In contrast, zolpidem clearance was lower in women than in men (3.5 versus 6.7 ml/min/kg, P < .06). Compared to placebo, both
active medications produced significant benzodiazepine agonist-like
pharmacodynamic effects: sedation, impaired psychomotor performance,
impaired information recall, and increased electroencephalographic
-amplitude. Effects of triazolam and zolpidem in general were
comparable and less than 8 h in duration. There was no evidence of
a substantial or consistent sex difference in pharmacodynamic effects
or in the kinetic-dynamic relationship, although subtle differences could not be ruled out due to low statistical power. The complete dependence of triazolam clearance on CYP3A activity, as opposed to the
mixed CYP participation in zolpidem clearance, may explain the
differing sex effects on clearance of the two compounds.
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Introduction |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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The
influence of sex (gender) on the pharmacokinetics and pharmacodynamics
of psychotropic drugs is an issue of current scientific and clinical
concern. A number of recent reviews have considered whether the
expression and/or activity of various CYP enzymes may differ between
men and women, thereby leading to differences in pharmacokinetics that
are not explained by sex-dependent differences in body weight (Dawkins
and Potter, 1991
; Yonkers et al., 1992; Harris et al., 1995; Pollock,
1997). Much of the research focuses on the CYP3A isoforms, known to be
partially or entirely responsible for the biotransformation of many
psychotropic drugs (von Moltke et al., 1995; Thummel and Wilkinson,
1998). Some studies suggest that CYP3A activity may be higher in women
than in men, leading to higher clearances of some CYP3A substrates in
women (Greenblatt et al., 1994; Gorski et al., 1998; Schroeder et al.,
1998). The differences may be more evident for orally administered
CYP3A substrates that ordinarily undergo extensive presystemic
extraction, with a significant apparent contribution of CYP3A isoforms
located in gastrointestinal tract mucosal cells. However, the
experimental data on this topic are not consistent, and there is much
conflicting evidence. Also of concern are possible sex-dependent
differences in intrinsic drug sensitivity, although data on this topic
are sparse.
Anxiolytic and hypnotic medications that are benzodiazepine receptor
agonists continue to be extensively prescribed in clinical practice for
the treatment of anxiety, panic disorder, and sleep disorders. Until
the early 1990s, essentially all such medications had a benzodiazepine
structure and were full-agonist 
-aminobutyric acid-benzodiazepine
receptor ligands (Hollister et al., 1993; Shader and Greenblatt, 1993).
The imidazopyridine derivative zolpidem was introduced into clinical
practice as a hypnotic agent a number of years ago and now is widely
used throughout the world (Langtry and Benfield, 1990; Hoehns
and Perry, 1993; Undén and Roth-Schechter, 1996; Darcourt et al.,
1999). Although not a benzodiazepine in structure, zolpidem is a
-aminobutyric acid-benzodiazepine receptor agonist with relative
selectivity for the type 1 benzodiazepine receptor subtype (Sanger et
al., 1994). The clinical importance of this neuropharmacological
property is controversial (Lobo and Greene, 1997; Rush, 1998). Most
clinical studies comparing the pharmacodynamic properties of zolpidem
with those of a typical nonselective full-agonist benzodiazepine such
as triazolam do not detect consistent pharmacodynamic differences after
comparably potent single doses (Berlin et al., 1993; Rush and
Griffiths, 1996; Mattila et al., 1998; Rush et al., 1998; Mintzer and
Griffiths, 1999). Nor are there consistent differences between zolpidem
and triazolam in hypnotic efficacy during treatment of sleep disorders (Nowell et al., 1997). Zolpidem, like triazolam, has a short
elimination half-life (Durand et al., 1992; Salvà and Costa,
1995; Greenblatt et al., 1998a) and has low likelihood of producing
residual daytime sedation after nighttime administration (Undén
and Roth-Schechter, 1996). Some data indicate that zolpidem has a
reduced likelihood of producing discontinuation or withdrawal phenomena
after treatment is stopped (Monti et al., 1994; Ware et al., 1997).
Another distinguishing property of zolpidem is that its
biotransformation is only partially (about 60%) mediated by CYP3A
(Pichard et al., 1995; von Moltke et al., 1999), whereas
clearance of triazolam is fully dependent on CYP3A (von Moltke et al.,
1996). As a consequence, coadministration of strong CYP3A inhibitors
such as ketoconazole or itraconazole produces far less impairment of
zolpidem clearance than of triazolam clearance (von Moltke et al.,
1996; Greenblatt et al., 1998a,b).
The present study compared the kinetics and dynamics of single clinically comparable doses of triazolam and zolpidem in healthy young male and female volunteers. The objectives were to evaluate the comparative pharmacodynamics of the two compounds using a variety of subjective and objective measures of benzodiazepine agonist activity and to assess possible sex-dependent differences in the kinetics and responses to both drugs.
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Materials and Methods |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Subjects and Procedure. The study protocol was reviewed and approved by the Human Investigation Review Committee serving Tufts University School of Medicine and New England Medical Center. Male and female volunteers, aged 22 to 41 years, participated after giving written informed consent. All were healthy ambulatory adults, with no evidence of medical disease and receiving no other medications. Females were not taking oral contraceptives.
Subjects participated in a four-way crossover study. To allow volunteers to adapt to the study setting and procedures and to minimize the effects of practice, the first treatment in the sequence was a single-blind administration of placebo; data from this practice trial were not used in subsequent analyses. The next three treatments were double-blind and randomized in sequence. The three conditions were placebo, 0.25 mg triazolam, and 10 mg zolpidem. At least 7 days elapsed between treatments. All medications were identically packaged. On the morning of each study day, after ingesting a standardized light breakfast with no caffeine-containing food or beverages and no grapefruit juice, subjects arrived at the Research Unit at approximately 7:30 AM. They fasted until 12:00 noon, after which they resumed a normal diet (without grapefruit juice or caffeine-containing food or beverages). The single dose of the study medication was given with 240 ml of tap water at 9:00 AM. Venous blood samples were drawn from an indwelling cannula into heparinized tubes prior to dosing and at the following postdosing times: 0.5, 1.0, 1.5, 2.0, 2.5, 3, 4, 5, 6, 8, and 24 h. Samples were centrifuged, and the plasma was separated and frozen until the time of assay. The electroencephalogram (EEG) was recorded using a six-electrode montage, with instrumentation and methodology described previously (Greenblatt et al., 1994, 1998a,b; von Moltke et al., 1996). At two
predosing times and during 8 h postdosing at times corresponding
to blood sampling, the EEG was quantified in 4-s epochs for as long as
necessary to ensure at least 2 min of artifact-free recording. Data
were digitized over the power spectrum from 4.0 to 31.75 cycles/s (Hz)
and then fast Fourier-transformed to determine amplitude over the 4.0- to 31.75-Hz spectrum and in the (13.0-31.75 Hz) band.
Subjects' self-ratings of sedative effects and mood state were
obtained using a series of 100-mm visual-analog scales (Scavone et al.,
1998). Ratings of sedation were also performed by trained observers,
using the same rating instrument, without knowledge of the treatment
condition. Self- and observer ratings were obtained twice before
medication administration and at postdosing times indicated earlier.
The digit symbol substitution test (DSST) was administered twice prior
to dosing and at times corresponding to rating scales (Greenblatt et
al., 1991, 1994, 1998a,b; von Moltke et al., 1996). Subjects were asked
to make as many correct symbol-for-digit substitutions as possible
within a 2-min period. Subjects completed equivalent DSST variants,
with no individual taking the same test more than once.
Acquisition and recall of information were evaluated using a word-list
free recall procedure that was administered at 1.5 h after drug or
placebo administration (Greenblatt et al., 1991, 1994, 1998a,b; von
Moltke et al., 1996). Sixteen words, taken from four different
categories, were read in random order in "shopping-list" fashion.
Subjects wrote down items immediately after lists were presented in
random order. List presentation and recall were repeated a total of six
times at 1.5 h after dosing. At 24 h after dosing, subjects
were asked to remember as many words as possible from the previous
day's list (delayed or "free" recall). Thereafter, the same lists
were read in the same sequence in which they were presented on the
previous day to assess whether residual effects of drug administration
on immediate recall were detectable.
Analysis of Data.
Plasma concentrations of triazolam were
determined by gas chromatography with electron-capture detection,
having a sensitivity limit of 0.2 ng/ml for a 2-ml sample (von Moltke
et al., 1996). The variance for replicate samples did not exceed 7%,
and the between-day variance for a quality control sample was 4.3%.
Plasma concentrations of zolpidem were determined by HPLC with
fluorescence detection (Durol and Greenblatt, 1997). The sensitivity
limit was 1 to 2 ng/ml, and the variance between replicate samples did not exceed 8%.
) of the terminal log-linear phase of each triazolam or
zolpidem plasma concentration-versus-time curve was determined by
linear regression analysis. This slope was used to calculate the
apparent elimination half-life. Area under the plasma concentration curve from time 0 until the last detectable concentration was determined by the linear trapezoidal method. To this area was added the
residual area extrapolated to infinity, calculated as the final
concentration divided by , yielding the total area under the plasma
concentration-versus-time curve (AUC). The peak plasma concentration
and the time of peak concentration represented the rate of appearance
of drug in systemic circulation. Apparent oral clearance was calculated
as the administered dose divided by the total AUC. Since triazolam or
zolpidem was not detectable in the 24-h plasma samples, calculation of
pharmacokinetic parameters was based on an 8-h duration of sampling.
For some subjects, the duration of sampling during the terminal phase
did not exceed three times the estimated half-life. This is a potential
weakness in the pharmacokinetic methodology.
For self- and observer ratings on visual-analog scales, the two
predosing baseline ratings were averaged, and postdosing scores were
expressed as the increment or decrement relative to the mean predosing
value. Scores on the DSST were analyzed similarly. The word-list memory
test was analyzed as the mean absolute number of words correctly
remembered for delayed recall and as mean number of words remembered
after six trials for immediate recall.
For each EEG recording session, the relative -amplitudes ( divided by total, expressed as percent) were calculated, and values
from the left and right frontotemporal leads were averaged. The means
of the relative -amplitudes in the predosing recordings were used as
baseline, and all postdosing values were expressed as the increment or
decrement over that treatment's mean predosing baseline value.
For each pharmacodynamic variable, the area under the 4-h plot of
effect change score versus time was calculated to obtain a single
integrated measure of pharmacodynamic action during the period of
greatest drug effect. The ratio (RAUC) of 4-h pharmacodynamic effect
area divided by area under the plasma concentration curve was used as a
measure of drug sensitivity and compared between men and women for
triazolam and zolpidem treatment conditions.
Mean values of pharmacodynamic effects at individual time points were
evaluated in relation to plasma concentrations at corresponding times
using kinetic-dynamic modeling procedures, with or without incorporation of a rate constant [KEO
(first-order rate constant representing exit of drug from hypothetical
effect compartment)] describing the apparent equilibration delay
between drug concentrations in plasma and at a hypothetical "effect
site" (Greenblatt et al., 1994; Laruijssens and Greenblatt, 1996).
Statistical procedures included linear and nonlinear regression ANOVA
including post hoc Student-Newman-Keuls multiple comparisons. Analyses
were performed using all subjects together and with male and female
subjects analyzed separately. For evaluation of overall treatment
effects on pharmacodynamic variables, the study was statistically
powered (
= 0.05, power = 0.80) to detect clinically important benzodiazepine agonist effects as described previously (Greenblatt et at, 1991, 1994, 1998a,b; von Moltke et al., 1996). The
statistical power of comparisons between men and women in kinetic or
dynamic variables allowed detection of differences equivalent in
magnitude to those expected for treatment contrasts.
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Results |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Clinical Effects. Two subjects withdrew from the study because of nausea developing at 1 to 2 h after zolpidem administration; they were replaced with two other subjects. Data analysis represents the 18 participants that completed all treatment conditions. Characteristics are shown in Table 1.
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Pharmacokinetics.
Triazolam attained peak plasma concentration
on average at 1.25 h after dosing (Table 1, Fig.
1). The mean elimination half-life was
2.7 h, with a range of 1.8 to 3.9 h. Sex did not
significantly influence elimination half-life. Oral clearance of
triazolam, both with and without normalization for body weight, was
higher in women than in men; however, there were large individual
variations within each group, and differences were not statistically
significant.
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Pharmacodynamic Effects. ANOVA indicated no significant differences among the three treatments in predosing baseline values of any of the pharmacodynamic variables.
Triazolam and zolpidem both produced pharmacodynamic effects consistent with benzodiazepine receptor agonism. These effects included increased EEG amplitude in the-frequency range, impaired performance on the DSST, and increases in self-ratings and observer ratings of sedation (Figs. 2 and
3). These effects were of relatively short duration; by 4 to 8 h after dosing, values were generally indistinguishable from those associated with placebo. Placebo itself
produced no evidence of benzodiazepine agonist activity.
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Kinetic-Dynamic Relationships.
Evaluation of mean
pharmacodynamic effect change scores versus mean plasma triazolam
concentrations at corresponding times indicated evidence of
counterclockwise hystereses, consistent with a delay in equilibration
of triazolam between plasma and hypothetical effect site. Based on the
aggregate data for all subjects, the mean value of apparent half-life
of equilibration corresponding to KEO
(t1/2KEO) was 10.2 min when EEG
-amplitude was used as the pharmacodynamic effect variable (Fig.
6). Hypothetical effect site triazolam
concentrations were significantly related to EEG effect change measures
using an exponential concentration-effect link model (Laurijssens and
Greenblatt, 1996). When male and female subjects were evaluated
separately, t1/2KEO values were 8.4 and 10.0 min, respectively (Fig. 6). Corresponding
t1/2KEO values were 11.0 min using DSST
change score as the effect measure and 12.7 min using observer-rated
sedation as the effect measure. When male and female subjects were
evaluated separately, resulting t1/2KEO
values were not significantly different.
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Discussion |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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The triazolobenzodiazepine triazolam is a "pure" substrate for
human CYP3A, being metabolized to its -hydroxy and 4-hydroxy metabolites solely by isoforms of this subfamily (von Moltke et al.,
1996). Crossover studies of i.v. and oral triazolam in healthy volunteers indicate that its oral bioavailability averages 40 to 50%
(Kroboth et al., 1995). This is lower than the hepatic extraction ratio
calculated from clearance of i.v. triazolam together with typical
values of hepatic blood flow and indicates that gastrointestinal CYP3A
is likely to contribute to net presystemic extraction of orally
administered triazolam. In the present study, values of weight-normalized oral clearance of triazolam were higher in women than
in men. However, the difference did not reach statistical significance
due to the large individual variability within groups. We observed
similar nonsignificant differences between young men and women in three
previous studies of orally administered triazolam (Greenblatt et al.,
1983b, 1991; Smith et al., 1983); in a fourth study, oral clearance of
triazolam also was higher in women than in men, and the difference
reached statistical significance (Greenblatt et al., 1994). In other
studies of sex-dependent differences in kinetics of various CYP3A
substrates, significantly higher values of clearance of midazolam,
adinazolam, alprazolam, cyclosporine, and tirilazad in women compared
with in men were described (Kristjánsson and Thorsteinsson, 1991;
Fleishaker et al., 1992, 1995; Hulst et al., 1994; Gorski et al., 1998;
Schroeder et al., 1998; Tsunoda et al., 1999). In a number of reports
involving these and other CYP3A substrates (e.g., nefazodone,
trazodone, buspirone, and bromazepam), sex-related differences in
clearance were not significant (Greenblatt et al., 1983a, 1984, 1987;
Ochs et al., 1987; Gammans et al., 1989; Kirkwood et al., 1991;
Barbhaiya et al., 1996; Thummel et al., 1996; Kashuba et al., 1998).
Thus, the available literature does not support the conclusion that
values of clearance of CYP3A substrates are predictably higher in women
than in men. Although a trend in this direction is often observed,
differences only inconsistently reach significance, suggesting that sex
accounts for a relatively small component of the overall variability in clearance of drugs metabolized by CYP3A. When sex-related differences are significant, they generally are applicable to oral administration of high-extraction compounds such as midazolam or triazolam (Gorski et
al., 1998). This raises the possibility that the gastrointestinal tract
may constitute the principal site for sex-dependent variation in
expression and/or activity of CYP3A.
In contrast to triazolam, weight-normalized oral clearance of zolpidem
was higher in men than in women; the difference approached but did not
quite reach statistical significance. Zolpidem differs importantly from
triazolam in its metabolic and pharmacokinetic profile. CYP3A accounts
for approximately 60% of zolpidem clearance, with CYP2C9 and CYP1A2
accounting for the majority of the remaining fraction (Pichard et al.,
1994; von Moltke et al., 1999). Absolute bioavailability of oral
zolpidem averages 70% (Patat et al., 1994). While coadminstration of
ketoconazole, a relatively specific CYP3A inhibitor, with triazolam
greatly reduces triazolam clearance and increases AUC by 5-fold or
more, cotreatment of ketoconazole with zolpidem increased zolpidem AUC
by a factor of only 1.6 (von Moltke et al., 1996; Greenblatt et al.,
1998a,b). Previous studies have not clearly established an effect of
sex on zolpidem clearance, but there is a suggestion of higher values
of clearance in men as opposed to women (Durand et al., 1992;
Salvà and Costa, 1995). The mechanism of the apparently different
effects of sex on the kinetic profile of triazolam as opposed to
zolpidem is not established but may be related to the contribution of
CYP2C9 to zolpidem clearance and the relatively low presystemic
extraction of zolpidem.
The single-dose pharmacodynamic profiles of triazolam and zolpidem were
similar, based on a variety of well-validated testing procedures. Both
compounds produced sedative effects (as rated by subjects themselves
and by observers), impairment of performance on the DSST, and increased
amplitude in the -frequency range on the EEG. The time course and
quantitative intensity of the effects of the two drugs were similar,
and for both compounds pharmacodynamic effects were in general
indistinguishable from placebo by 8 h after dosing. Furthermore,
both triazolam and zolpidem produced anterograde amnesia, characterized
mainly by impaired recall of information acquired at or near the time
of maximum drug effect. All of these findings are consistent with
previous pharmacodynamic studies of these compounds (Berlin et al.,
1993; Rush and Griffiths, 1996; Lobo and Greene, 1997; Greenblatt et al., 1998a; Rush, 1998; Rush et al., 1998; Hintzer and Griffiths, 1999). However, on some subjective pharmacodynamic measures, zolpidem showed some unexpected properties, including effects greater than those
of triazolam on self-ratings of thinking slowed down and feeling
"spacey". Zolpidem also significantly increased self-ratings of
feeling "nervous", whereas placebo and triazolam were comparable. The mechanism of these apparently different properties of zolpidem, as
well as the reason for the two episodes of nausea (leading to study
discontinuation) in two subjects, are not established.
Taken together, the outcome of this and other single-dose
pharmacodynamic comparisons of zolpidem with triazolam and other typical full-agonist benzodiazepine receptor ligands suggests that
clinical consequences of the apparent receptor subtype selectivity of
zolpidem are not established (Lobo and Greene, 1997; Rush, 1998).
Similarly, no clear differences emerge between comparable doses of
zolpidem and triazolam with respect to hypnotic efficacy or residual
effects (Nowell et al., 1997), although some data indicate that
zolpidem (at nightly doses of 10 mg or less) is less likely to produce
rebound insomnia after discontinuation of treatment than is triazolam
at nightly doses of 0.25 mg (Monti et al., 1994; Ware et al., 1997).
An analysis of mean plasma concentrations of triazolam or zolpidem in
relation to mean values of pharmacodynamic change scores at
corresponding times indicated highly significant relationships predicted on linear or exponential functions. In the case of triazolam, the data were also consistent with an equilibration delay between plasma and the hypothetical effect site. This phenomenon has been reported in some previous studies of orally administered triazolam (Greenblatt et al., 1994) but not in others (Greenblatt et al., 1998b).
For both zolpidem and triazolam, there was no consistent evidence of a
sex-dependent difference in 4-h effect areas or RAUC values for any of
the pharmacodynamic variables, nor a difference in the kinetic-dynamic
relationships based on mean values at corresponding times. Thus, the
data do not indicate any important effect of sex on the pharmacodynamic
response to single doses of these two benzodiazepine receptor agonists.
However, because individual variability within groups proved to be
fairly high, the statistical power of comparisons between male and
female subjects was correspondingly low. We cannot rule out the
existence of small or subtle sex-dependent differences that would
require studies of much larger numbers of subjects to evaluate.
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Footnotes |
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Accepted for publication January 24, 2000.
Received for publication September 21, 1999.
1 This work was supported in part by Grants MH-34223, DA-05258, and RR-00054 from the Department of Health and Human Services and by a grant-in-aid from Pharmacia and Upjohn, Kalamazoo, Michigan. L.L.v.M. is the recipient of a Scientist Development Award (K21-MH-01237) from the Department of Health and Human Services.
Send reprint requests to: David J. Greenblatt, M.D., Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, 136 Harrison Ave., Boston, MA 02111. E-mail: dj.greenblatt{at}tufts.edu
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Abbreviations |
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EEG, electroencephalogram; DSST, digit symbol substitution test; AUC, area under the plasma concentration-versus-time curve; RAUC, area under pharmacodynamic effect curve divided by area under plasma concentration curve; KEO, first-order rate constant representing exit of drug from hypothetical effect compartment; t1/2KEO, apparent half-life of equilibration corresponding to KEO.
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References |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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