Pharmacokinetic and pharmacodynamic characterization of OROSA

and immediate-release amitriptyline

Suneel K. Gupta, Jaymin C. Shah & Stephen S. Hwang

Department of Clinical Pharmacology, ALZA Corporation, Mountain View, California, USA

Aims To characterize the pharmacokinetics of amitriptyline and its metabolite

nortriptyline following OROSA and IR treatments, and to correlate them with
anticholinergic side-effects.
Methods The pharmacokinetics and safety of amitriptyline following administration
of an osmotic controlled release tablet (OROSA and an immediate release (IR)
tablet were evaluated in 14 healthy subjects. In this randomized, open label, three-
way crossover feasibility study, the subjects received a single 75 mg OROSA tablet,
three 25 mg IR tablets administered every 8 h, or 325 mg IR tablets administered
at nighttime. In each treatment arm serial blood samples were collected for a period
of 84 h after dosing. The plasma samples were analysed by gas chromatography for
amitriptyline and its metabolite nortriptyline. Anticholinergic effects such as saliva
output, visual acuity, and subject-rated drowsiness and dry mouth were measured
on a continuous scale during each treatment period.
Results Following dosing with OROSA (amitriptyline hydrochloride), the mean
1
maximal plasma amitriptyline concentration Cmax (15.3 ng ml ) was lower and the
mean tmax (25.7 h) was longer than that associated with the equivalent IR dose
administered at nighttime (26.8 ng ml1 and 6.3 h, respectively). The bioavailability
of amitriptyline following OROSA dosing was 95% relative to IR every 8 h dosing,
and 89% relative to IR nighttime dosing. The metabolite-to-drug ratios after the
three treatment periods were similar, suggesting no change in metabolism between
treatments. The relationships between plasma amitriptyline concentration and
anticholinergic effects (e.g. reduced saliva weight, dry mouth, and drowsiness) were
similar with all three treatments. Of the anticholinergic effects, only decreased saliva
weight and dry mouth correlated well with plasma amitriptyline concentrations;
drowsiness did not. There was no apparent correlation between anticholinergic
effects and the plasma nortriptyline concentration.
Conclusions The bioavailability of OROSA (amitriptyline hydrochloride) was similar
to that of the IR treatments and the pharmacokinetics of amitriptyline after OROSA
dosing may decrease the incidence of anticholinergic effects compared with that
seen with nighttime dosing of the IR formulation. Therefore, this controlled-release
formulation of amitriptyline may be appropriate for single daily administration.
Keywords: amitriptyline, anticholinergic effects, controlled-release, pharmacodynam-
ics, pharmacokinetics

of noradrenaline re-uptake at the adrenergic nerve

Introduction
A tricyclic agent with sedative effects, amitriptyline, is
indicated for relief of the symptoms of depression.
Although its mechanism of action in man is not well
defined, amitriptyline is believed to be a potent inhibitor
Correspondence: Dr Suneel K. Gupta, Department of Clinical Pharmacology,
ALZA Corporation, 1550 Plymouth Street, PO Box 7210, Mountain View,
CA 940397210, USA.
Received 4 March 1998, accepted 22 February 1999.
endings [1]. Amitriptyline is not a monoamine oxidase
inhibitor, and its primary action does not involve
stimulation of the central nervous system. Amitriptyline
hydrochloride is currently available in an immediate-
release tablet and an injectable formulation. The total
daily adult dosage typically ranges from 75 to
150 mg day1 for outpatient use, but doses of 200
300 mg day1 are sometimes prescribed for hospitalized
patients.

1999 Blackwell Science Ltd Br J Clin Pharmacol, 48, 7178 71

S. K. Gupta et al.
Amitriptyline is completely but slowly absorbed from
the gastrointestinal tract after oral administration, and
peak plasma concentrations are usually reached in 48 h.
Amitriptyline undergoes extensive hepatic presystemic
elimination, and its systemic bioavailability ranges from
33% to 62% after oral administration [2]. A highly
lipophilic compound, amitriptyline is widely distributed
throughout the body and extensively bound to tissue and
plasma proteins [3]. About one-third to one-half of
the drug is excreted within 24 h. The plasma half-life
ranges from 10 to 28 h for amitriptyline and from 16
to 80 h for its active metabolite, nortriptyline [4, 5].
Amitriptylines most common side-effects, such as blurred
vision, dry mouth, and constipation, are due to its
anticholinergic effects. The sedative effect is thought to
be mediated by blockade of histamine receptors [6].
Amitriptyline in high doses also has some cardiac effects,
such as dysrhythmias, sinus tachycardia, and prolonged
conduction time.
Schulz et al. [2] reported that a single dose (80100 mg )
of amitriptyline given to healthy volunteers was not well
tolerated, suggesting that a gradual buildup in plasma
amitriptyline concentration is preferable. The total daily
dose may be given in divided doses, or once at nighttime
to take advantage of the drugs known sedative effect.
When administered at nighttime amitriptyline has been
well tolerated with few side-effects [7, 8].
An OROSA system has been developed to deliver
75 mg amitriptyline hydrochloride by a membrane-
controlled, osmotic process for 2224 h. The resultant
slow increase in plasma amitriptyline concentration is
intended to decrease the incidence of anticholinergic
effects commonly experienced with peak plasma drug
concentrations. The two-compartment core of each
OROSA (amitriptyline hydrochloride) tablet contains the
water-soluble drug amitriptyline hydrochloride in a drug
compartment and inactive excipients in an osmotic push
layer compartment. These components are enclosed
within a cellulosic membrane that is permeable to water
but impermeable to ions or to the drug.
The objectives of this feasibility study were to
characterize the pharmacokinetics of amitriptyline and its
metabolite nortriptyline following OROSA and IR
treatments, and to correlate them with the anticholi-
nergic effects.
Methods
Subjects
Fifteen healthy male subjects, 2137 years (mean 29 years),
with a mean weight of 77.4 kg (6194 kg), were enrolled
in the study.
This feasibility study protocol was reviewed and
72
approved by the Institutional Review Board of Harris
Laboratories (Lincoln, NE), where the clinical portion of
the study was conducted. Written informed consent was
obtained from each subject before entry. Inclusion criteria
were as follows: body weight within 15% of the ideal
weight for the subjects height, based on MetLifeA;
normal physical examination; and no clinically significant
deviations in clinical and laboratory tests (vital signs,
haematology, blood chemistry, and urinalysis). None of
the subjects had smoked cigarettes for at least 3 months
before study entry.
Subjects fasted for 10 h before and 4 h after the first
dose of each treatment. All subjects refrained from
consuming alcohol for 3 days before and during the study
period. Caffeine-containing beverages were prohibited
while subjects were at the study centre.
Study design
This was a randomized, open-label, three-way crossover
study. The three treatments were as follows: 75 mg
OROSA (amitriptyline hydrochloride) administered at
06.00 h; 25 mg ElavilA administered three times a day at
06.00 h, 14.00 h, and 22.00 h; and three 25 mg ElavilA
administered at 22.00 h. The washout period between
treatments was 14 days. Two days before receiving the
first treatment, subjects were enrolled in the centre so
that baseline measurements for anticholinergic effects
(e.g. salivary flow rate, drowsiness and feeling of dry
mouth) could be obtained over a period of 24 h. After
the baseline measurements were taken, the subjects
received their first treatment the following morning or at
nighttime according to the randomization schedule. Each
dose was taken with 240 ml of water. Subjects were
instructed to swallow each tablet whole and not to chew,
crush, or divide it, and to drink at least 8 cups of water
per day. Standardized meals were served during the study
period (breakfast at 07.00 h, lunch at 12.00 h, dinner at
18.00 h, and a snack at 21.00 h); for subjects receiving
the IR treatment at nighttime, snack was not given.
Subjects remained in the clinic 4860 h after the initial
dose, and they were instructed to return to the clinic for
the remaining blood draws and measurements.
Assessments
Safety Treatment safety assessments included blood
pressure and heart rate measurements, which were taken
before and at predetermined times throughout the study.
In addition, laboratory parameters were assessed before
and at the end of the study. Adverse events volunteered
by subjects were also recorded.
1999 Blackwell Science Ltd Br J Clin Pharmacol, 48, 7178

Anticholinergic effects Saliva output, dry mouth ratings,
and visual acuity following each treatment were assessed
at specific times during the study. The assessment times
for saliva output and dry mouth were predose, 1, 2, 4, 6,
8, 12, 16, 24, 30, 36, 48, 60, 72 and 84 h post dosing.
Likewise visual acuity test was done at predose, 8 and
16 h post dosing. Drowsiness ratings were obtained only
for the OROSA (amitriptyline hydrochloride) and the
IR every 8 h treatments. Because the IR nighttime
treatment involved frequent awakenings for blood sample
collection after dosing, drowsiness ratings were not
solicited in this group.
At specific times during the study, the subjects rated
their dry mouth sensation on a 100 mm Visual Analogue
Scale (VAS) (0=normally moist; 100=extremely dry).
Dry mouth assessments were done before the saliva
output test.
The stimulated saliva output measurement was a
modification of earlier published methods [9, 10]. The
subject was asked to swallow his saliva just before the
test. A drop of 1% citric acid was placed on his tongue;
he was instructed not to swallow for 2 min and then to
spit the saliva into a clean, dry, preweighed beaker.
The sedation ratings were done at specific times during
the study, and the subjects gave their subjective assessments
of drowsiness using a 100 mm VAS (0=extremely alert;
100=extremely drowsy). Subjects who fell asleep during
the 06.00 h22.00 h period were given the maximal
score (100) for that period.
Visual function was assessed before dosing and at 8 and
16 h after the dose; near and far vision were evaluated
using the near vision card and the Snellen eye chart,
respectively.
Pharmacokinetics methods
Following dosing of each treatment, serial blood samples
for pharmacokinetic evaluation of amitriptyline and
nortriptyline were collected immediately before dosing
and for a period of 84 h after administration of the dose.
The plasma samples were analysed for determination
of amitriptyline and nortriptyline using a gas chromatogra-
phy method. Amitriptyline, nortriptyline, and an internal
standard, desipramine, were extracted from the alkaline
plasma into a hexanol/butanol mixture. The hexanol/
butanol phase was then back-extracted with hydrochloric
acid. The acid phase was made alkaline, followed by
extraction with butyl acetate. Analysis was done by gas
chromatography with nitrogen phosphorous detection.
This method was validated with a minimum quantifi-
able concentration of 0.5 ng ml1 for amitriptyline and
nortriptyline. The samples were kept frozen at 20 C
before analysis, and a 1ml sample was used for analysis.
The day to day variability in measurements of quality
1999 Blackwell Science Ltd Br J Clin Pharmacol, 48, 7178
OROS and immediate release amitriptyline
control samples for amitriptyline and nortriptyline was
<7.0%.
Model independent methods were used to determine
the following pharmacokinetic parameters for amitripty-
line and nortriptyline: the maximum observed plasma
concentrations (Cmax ) and the corresponding sampling
time (tmax ), the terminal or disposition rate constant (lz ),
and the terminal or disposition half-life (t1/2 ). The area
under the curve to the last sample collection point
(AUC(0,t)) was computed using the linear trapezoidal rule,
and the AUC value extrapolated to infinity (AUC(0,00))
was determined as the sum of AUC(0,t) plus the area
extrapolated to infinity, calculated by the concentration
at time t (Ct) divided by lz. In addition the relative
bioavailability ( F) of OROS (amitriptyline hydrochloride)
was also computed using the IR every 8 h as the reference
treatment.
Pharmacodynamics
For each treatment, plasma concentration and anticholi-
nergic effects across all subjects were averaged at each
sample collection time. The means of selected anticholi-
nergic effects (decreased saliva production, drowsiness,
and dry mouth) were correlated to plasma amitriptyline
and nortriptyline concentrations. The data were fitted to
the sigmoidal Hill equation using the nonlinear regression
method in SAS:
EmaxCt
c
Et=E0
C50+Ct
c c
where:
Et=value (weight or rating ) of the observed effect at
time t
E0=baseline value (weight or rating)
EC50=plasma drug concentration required to produce
50% of the maximum effect
Emax=maximum effect (weight or rating) observed
Ct=plasma drug concentration at time t
c=Hill coefficient
An alternative method for correlating drug concentration
with anticholinergic effects was pursued by normalizing
(linear transformationz score) the anticholinergic effects
toward the mean value and correlating this with plasma
amitriptyline concentration. The advantage of transform-
ation to z score is it enables comparison of plasma
concentration and different measures of the anticholi-
nergic effects in the same domain. The slopes of plots
were compared to evaluate which anticholinergic effect
73
S. K. Gupta et al.

correlated best to the plasma concentration. The effects
were normalized as below:
Enor=(EobsEmean )/Esd
where:
Enor=normalized (around mean) effect
Eobs=observed effect
Emean=mean of Eobs
Esd=standard deviation (s.d.) of Eobs
Statistics
Phamacokinetic parameters for the three treatments were
compared using an analysis of variance model (anova)
appropriate for a crossover study design. The statistical
computer package PCSAS version 6.10 (SAS Institute,
NC, USA) was used for statistical analysis. The variance
model included terms for treatment, subject within
sequence, treatment sequence, and period.
Results
Pharmacokinetics
Baseline measurements were completed for 15 subjects.
One subject was withdrawn from the study before
receiving any study medication because he admitted that
he was a smoker. The baseline value for this subject was
excluded from analysis. The remaining 14 subjects
completed the study.
As presented in Table 1 and Figure 1, for the reference
treatment i.e., IR every 8 h dosing, the plasma amitripty-
line concentrations increased rapidly after the second
hour of each of the first two doses and a mean maximum
concentration of 19 ng ml1 occurred about 6 h after
dosing. The mean half-life value for amitriptyline
following the every 8 h treatment was 19.4 h and the
1
corresponding AUC(0, 2) was 661 ng ml h.
Following the OROSA (amitriptyline hydrochloride)
administration, the plasma amitriptyline concentrations
increased slowly, with a mean maximum concentration
of 15.3 ng ml occurring at 25.7 h (tmax ) and the half-life
value of amitriptyline was reported to be 20.4 h. The
1
mean AUC(0, 2) was 593 ng ml h. Similarly,
following the nighttime dosing the mean maximum
amitriptyline concentration was 26.8 ng ml1, and the
corresponding AUC(0, 2) was 688 ng ml1 h. The
relative amitriptyline bioavailability with OROSA (ami-
triptyline hydrochloride) compared with IR nighttime
and IR every 8 h treatments were 89% (90% CI
77%102%) and 95% (90% CI 82%108%), respectively.
The plasma nortriptyline concentrations exhibited a
similar pattern to the parent drug amitriptyline after the
three treatments, with maximal nortriptyline concen-
1
tration of 12 ng ml occurring after the IR nighttime
treatment and the most delayed tmax of 34.6 h observed
with OROSA (amitriptyline hydrochloride) treatment
(Table 2 and Figure 2). The mean apparent elimination
half-life values for nortriptyline were similar among all
three treatments and ranged from 33 to 44 h. The mean
nortriptyline AUC(0,t) was the highest following the
nighttime treatment: 498 ng ml1 h, as compared with
1
329 ng ml h following OROSA (amitriptyline hydro-
chloride) treatment.
The mean metabolite-to-drug AUC(0, 2) values for
the OROSA (amitriptyline hydrochloride), IR every 8 h,
and IR nighttime treatments were 0.91, 1.02, and 1.0,
respectively, and were not significantly different from
each other ( P=0.37). Therefore, the extent of formation
and elimination of nortriptyline was similar after each of
the three treatments.
Anticholinergic effects
The mean ratings for dry mouth during the IR every
8 h and OROSA (amitriptyline hydrochloride) treatments
were not significantly different from baseline or from
each other. However, the mean ratings during the IR
nighttime treatment were significantly higher than those
associated with the other two treatments and the mean
baseline values except 24 h after administration.

Table 1 Pharmacokinetic parameters of

OROSA amitriptyline following administration of
Parameter (amitriptyline hydrochloride) IR every 8 h IR (nighttime) amitriptyline: OROSA (amitriptyline
hydrochloride), immediate release every
1
Cmax (ng ml ) 15.3 (7.0) 19.1 (6.0) 26.8 (7.5) 8 h (IR every 8 h) and immediate release
tmax (h) 25.7 (5.8) 17.0 (8.0) 6.3 (2.6) (IR) at nighttime. Values are mean (s.d.).
a
t1/2,z (h) 20.4 (4.3) 19.4 (5.3) 23.7 (6.7)
1 a
AUC(0, t) (ng ml h) 528 (197) 606 (220) 622 (176)
1
AUC(0, 2) (ng ml h)a 593 (229) 661 (246) 688 (211)
F (%) 89.3 (28.5) 96.2 (19.9) REF
F (%) 94.9 (30.8) REF 107.8 (20.5)

a
Means of all three treatments are not significantly different ( P<0.05) from each other.

74 1999 Blackwell Science Ltd Br J Clin Pharmacol, 48, 7178

 OROS and immediate release amitriptyline

Figure 1 Mean (s.d.) observed

plasma amitriptyline
concentrations following
administration of OROSA
(%, amitriptyline hydrochloride),
immediate release every 8 h
(6, IR every 8 h) and
immediate release at nighttime
(#) (n=14).

Table 2 Pharmacokinetic parameters of

nortriptyline following administration of OROSA
amitriptyline: OROSA(amitriptyline Parameter (amitriptyline hydrochloride) IR every 8 h IR (nighttime)
hydrochloride), immediate release every
1
8 h (IR every 8 h) and immediate release Cmax (ng ml ) 8.5 (5.6) 9.6 (3.5) 12.0 (3.6)
(IR) at nighttime. Values are mean (s.d.). tmax (h) 34.6 (11.1) 29.6 (1.6) 14.6 (7.2)
t1/2,z (h)a 43.5 (20.4) 38.8 (10.5) 32.9 (8.2)
1 b
AUC(0, t) (ng ml h) 329 (118) 436 (155) 498 (200)
1 b
AUC(0, 2) (ng ml h) 507 (245) 635 (339) 648 (309)
a
Metabolite/Drug AUC ratio 0.91 (0.43) 1.02 1.0 (0.41)
(0.42)

a
Means of all three treatments are not significantly different from each other ( P<0.05)).
b
Means of OROSA and IR every 8 h are not different from each other but both are different
from IR (nighttime ( P<0.05).

Mean weights of saliva produced after stimulation
during OROSA (amitriptyline hydrochloride) and IR
every 8 h treatments were not significantly different from
each other or from the mean baseline values for most
periods analysed. During IR nighttime treatment, the
mean amount of saliva produced was significantly less
than at baseline or during the other two treatments for
most periods. The mean weight of saliva produced was
observed to be the lowest following the IR nighttime
dosing with a drop of 65% from baseline at 8 h after
dosing, which was sustained for about 16 h after dosing
when it was still only 50% of the baseline observation.
The mean drowsiness values for the OROSA (amitrip-
tyline hydrochloride) and the IR every 8 h treatments
were not significantly different from each other but
were significantly increased from baseline at the 8 h
measurement.
A minor, clinically insignificant decrease in visual
acuity was observed after each of the three treatments as
compared with baseline values. Seven subjects during
OROSA (amitriptyline hydrochloride) and IR every 8 h
treatments and five subjects during the IR nighttime
treatments experienced this effect.
Concentration-effect relationship
After the IR nighttime dosing, the peripheral anticholi-
nergic effect (saliva production) was most reduced (65%)
from baseline at the 8 h measurement when the amitripty-
1
line concentration was about 25 ng ml ; this reduction

1999 Blackwell Science Ltd Br J Clin Pharmacol, 48, 7178 75

S. K. Gupta et al.

Figure 2 Mean (s.d.)

observed plasma nortriptyline
concentrations following
administration of OROSA
(%, amitriptyline
hydrochloride), immediate
release every 8 h (6, IR
every 8 h) and immediate
release at nighttime (#)
(n=14).

was sustained until 16 h. In contrast, after OROSA Table 3 Estimates of pharmacokinetic-pharmacodynamic

(amitriptyline hydrochloride) and IR every 8 h dosing, parameters for the anticholinergic effects following the three study
the decrease in saliva production was less profound, and treatments (n=14). Data are presented as mean, where E0 is the
1 baseline value, Emax is the maximal effect (weight or rating )
plasma drug concentrations were in the 715 ng ml observed, EC50 is the plasma drug concentration required to
range. Similarly, highest dry mouth ratings were observed produce 50% of the maximal effect, and c is the Hill coefficient.
after nighttime dosing and were statistically different from
baseline complementing the observation of decreased Parameter Saliva Dry mouth Drowsiness
saliva production after the IR nighttime dosing of
amitriptyline. E0 1.2 g 30.7 mm 38.2 mm
In summary, the subjective ratings for each of the Emax 0.9 g 60.2 mm 15.0 mm
1 1 1
EC50 14.7 ng ml 30.3 ng ml 3.1 ng ml
anticholinergic effects such as dry mouth, drowsiness and
c 1.0 1.7 1.0
saliva weights vs plasma amitriptyline concentration
profile for each treatment exhibited similar pattern and Normalized anticholinergic effects
were almost identical for most of the subjects. The mean Slope 0.100 0.103 0.096
weight of saliva produced decreased, and the mean of the SE of slope 0.019 0.019 0.040
subjective scores for dry mouth and drowsiness increased
as plasma amitriptyline concentrations increased. None of
1
the anticholinergic effects appeared to be correlated with estimated to be 30 ng ml , which is very close to the
the plasma nortriptyline concentrations. mean Cmax value observed after the nighttime dose of
1
The plasma amitriptyline concentrations and the 325 mg IR tablet (26.8 ng ml ). This implies that
corresponding anticholinergic effects of all treatments the observed dry mouth effect is only half of the maximal
were pooled together to get a better estimate of the effect. Based on the best-fit model, the maximum drop
model parameters. The pooled data were fitted to the in saliva would be to 0.9 g, at a plasma drug concentration
1
sigmoidal Emax model, and the parameters are listed in of about 30 ng ml .
Table 3. As shown in Figure 3, saliva weight measure- Alternatively, comparison of the slopes of the z-score
ments and dry mouth assessments correlated well to values and plasma amitriptyline concentrations for each
plasma amitriptyline concentrations, whereas drowsiness of the anticholinergic effects, showed that although the
assessments did not. The plasma drug concentration slopes were similar for all three effects, the standard error
required for 50% of the maximal dry mouth effect was of the slope for drowsiness vs concentration was the

76 1999 Blackwell Science Ltd Br J Clin Pharmacol, 48, 7178

 OROS and immediate release amitriptyline

2.5 3.0
2.5
2.0
2.0 1.5
1.0

Saliva
0.5
0.0
Saliva (g)

1.5 0.5
1.0
1.5
1.0 2.0
2.5
3.0
0.5
0 5 10 15 20 25 30

0.0 3.0
0 5 10 15 20 25 30 2.5
2.0
1.5

Dry mouth
1.0
70 0.5
0.0
60 0.5
1.0
1.5
Dry mouth (mm)

50 2.0
2.5
40 3.0

30 0 5 10 15 20 25 30

20 3.0
2.5
10 2.0
1.5
Drowsiness

0 1.0
0.5
0 5 10 15 20 25 30 0.0
0.5
1.0
1.5
70 2.0
2.5
60 3.0
Drowsiness (mm)

50 0 5 10 15 20 25 30
Plasma amitriptyline concentration (ngml1)
40
Figure 4 Relationship of plasma amitriptyline concentrations to
30 the normalized anticholinergic effects following the three study
treatments: OROSA (amitriptyline hydrochloride), immediate
20
release every 8 h (IR every 8 h) and immediate release of night
10 time (IR HS).

0
0 5 10 15
Plasma amitriptyline concentration (ngml1)
Figure 3 Predicted and mean observed plasma amitriptyline
concentrations and anticholinergic effects following the three
study treatments: OROSA (#, amitriptyline hydrochloride),
immediate release every 8 h (6, IR every 8 h) and immediate
release at nighttime ($, IR HS).
highest and least correlating compared with that of the
other two effects (Figure 4). The range of amitriptyline
concentration for drowsiness comparison was too narrow
compared with that of other anticholinergic effects, to
establish a reasonable concentration-effect relationship. In
contrast, the dry mouth and saliva weight effects correlated
well with plasma drug concentration and seemed to be
similarly sensitive to changes in drug concentration.
20 Discussion
The sustained-release characteristic of OROSA (amitrip-
tyline hydrochloride) was confirmed by the relatively flat
plasma concentration of amitriptyline for 36 h after
dosing. The absorption of amitriptyline was not only
sustained but also delayed, with undetectable amitriptyline
concentrations for 46 h after dosing, which was attri-
buted to the slow release characteristics of amitriptyline
from OROSA. A similar pattern was also observed for
nortriptyline. After IR nighttime dosing, the mean plasma
amitriptyline concentration increased rapidly, peaked at
6 h (27 ng ml1 ), and was maintained consistently higher
compared with the other treatments for a period of
1624 h. Minimal change in the drug to metabolite ratio
was observed for the two formulations in the study.

1999 Blackwell Science Ltd Br J Clin Pharmacol, 48, 7178 77

S. K. Gupta et al.
Amitriptyline undergoes extensive hepatic metabolism
following IR administration, however, due to the
extended release characteristics of OROSA it seems the
extent of metabolism is independent of the site of release
of the drug from the formulation, thereby resulting in
similar drug to metabolite ratio. However, the three
treatments results in very different concentration effect
time profiles, this could be due to the sensitivity of these
anticholinergic effects to the drug concentration in the
body. The peripheral anticholinergic effect (decreased
saliva production) was greatest after the IR nighttime
dosing, with a 65% drop from baseline in mean saliva
production at 8 h after dosing, when the plasma amitripty-
1
line concentration was about 25 ng ml . This effect
was sustained until 16 h after dosing, when the drop in
saliva production was still at 50% of the baseline
observation; this is consistent with reports by Schulz et al.
[2] after a single 80 to 100 mg dose of amitriptyline to
normal healthy subjects. In contrast, after the OROSA
(amitriptyline hydrochloride) and IR every 8 h dosing,
the decrease in saliva production was not as profound
and statistically not different from baseline after 8 h
following dosing, when the plasma amitriptyline concen-
1 4 Bowden CL, Koslow SH, Hanin I, Mass JW, Davis JM,
trations were maintained in the 715 ng ml range.
The overall concentration-effect relationship (using
EC50 and (values) is shown in Figure 3, the mean
observed data are superimposed on the predicted concen-
tration-effect curve. This demonstrates that the prediction
of the mean parameter estimates is reasonably accurate.
The minimum saliva rate that could be reached is 0.9 g
at a plasma amitriptyline concentration of about 30 ng
ml1. Similarly, the plasma drug concentration required
for 50% of the maximum dry mouth effect was estimated
1 amitriptyline. Clin Pharmacol Ther 1983; 33: 453459.
to be 30 ng ml , which correlates well with the higher
incidence of dry mouth ratings for the IR nighttime
treatment, because the plasma concentration after this
treatment is maintained at a relatively high level for a
longer period.
OROSA (amitriptyline hydrochloride) administration
resulted in lower and relatively well sustained plasma
amitriptyline concentrations compared with the other
two treatments in this study. Based on the concentration
effect analysis, it would be reasonable to anticipate a
lower incidence of unwanted anticholinergic effects after
OROSA administration compared with IR nighttime
treatment. This finding was also confirmed following
multiple dosing of OROSA and IR [11]. Better patient
compliance and greater tolerability because of a lower
78
incidence of adverse effects are possible benefits of
OROSA formulation.
In conclusion, based on this feasibility study the relative
bioavailability of OROSA (amitriptyline hydrochloride)
was similar to the two IR treatments and nortriptyline
formation also appeared to be similar amongst the
treatments. Some of the anticholinergic side-effects seem
to be concentration-related so those side-effects may be
reduced with a controlled release formulation. However,
these conclusions are based on a study in a small group
of healthy volunteers; the true clinical benefits of a
controlled release dosage formulation need to be demon-
strated in patients.
References
1 Therapeutic Drugs, ed. Sir Colin Dollery, Churchill
Livingstone, Edinburgh, 1991; A95A100.
2 Schulz P, Turner-Tamiyasu K, Smith G, et al. Amitriptyline
disposition in young and elderly men. Clin Pharmacol Ther
1983b; 33: 360366.
3 Cassano GB, Sjostrand SE, Hansson E. Distribution of 14C-
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