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

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


S. K. Gupta et al.

Amitriptyline is completely but slowly absorbed from approved by the Institutional Review Board of Harris
the gastrointestinal tract after oral administration, and Laboratories (Lincoln, NE), where the clinical portion of
peak plasma concentrations are usually reached in 48 h. the study was conducted. Written informed consent was
Amitriptyline undergoes extensive hepatic presystemic obtained from each subject before entry. Inclusion criteria
elimination, and its systemic bioavailability ranges from were as follows: body weight within 15% of the ideal
33% to 62% after oral administration [2]. A highly weight for the subjects height, based on MetLifeA;
lipophilic compound, amitriptyline is widely distributed normal physical examination; and no clinically significant
throughout the body and extensively bound to tissue and deviations in clinical and laboratory tests (vital signs,
plasma proteins [3]. About one-third to one-half of haematology, blood chemistry, and urinalysis). None of
the drug is excreted within 24 h. The plasma half-life the subjects had smoked cigarettes for at least 3 months
ranges from 10 to 28 h for amitriptyline and from 16 before study entry.
to 80 h for its active metabolite, nortriptyline [4, 5]. Subjects fasted for 10 h before and 4 h after the first
Amitriptylines most common side-effects, such as blurred dose of each treatment. All subjects refrained from
vision, dry mouth, and constipation, are due to its consuming alcohol for 3 days before and during the study
anticholinergic effects. The sedative effect is thought to period. Caffeine-containing beverages were prohibited
be mediated by blockade of histamine receptors [6]. while subjects were at the study centre.
Amitriptyline in high doses also has some cardiac effects,
such as dysrhythmias, sinus tachycardia, and prolonged
conduction time.
Study design
Schulz et al. [2] reported that a single dose (80100 mg )
of amitriptyline given to healthy volunteers was not well This was a randomized, open-label, three-way crossover
tolerated, suggesting that a gradual buildup in plasma study. The three treatments were as follows: 75 mg
amitriptyline concentration is preferable. The total daily OROSA (amitriptyline hydrochloride) administered at
dose may be given in divided doses, or once at nighttime 06.00 h; 25 mg ElavilA administered three times a day at
to take advantage of the drugs known sedative effect. 06.00 h, 14.00 h, and 22.00 h; and three 25 mg ElavilA
When administered at nighttime amitriptyline has been administered at 22.00 h. The washout period between
well tolerated with few side-effects [7, 8]. treatments was 14 days. Two days before receiving the
An OROSA system has been developed to deliver first treatment, subjects were enrolled in the centre so
75 mg amitriptyline hydrochloride by a membrane- that baseline measurements for anticholinergic effects
controlled, osmotic process for 2224 h. The resultant (e.g. salivary flow rate, drowsiness and feeling of dry
slow increase in plasma amitriptyline concentration is mouth) could be obtained over a period of 24 h. After
intended to decrease the incidence of anticholinergic the baseline measurements were taken, the subjects
effects commonly experienced with peak plasma drug received their first treatment the following morning or at
concentrations. The two-compartment core of each nighttime according to the randomization schedule. Each
OROSA (amitriptyline hydrochloride) tablet contains the dose was taken with 240 ml of water. Subjects were
water-soluble drug amitriptyline hydrochloride in a drug instructed to swallow each tablet whole and not to chew,
compartment and inactive excipients in an osmotic push crush, or divide it, and to drink at least 8 cups of water
layer compartment. These components are enclosed per day. Standardized meals were served during the study
within a cellulosic membrane that is permeable to water period (breakfast at 07.00 h, lunch at 12.00 h, dinner at
but impermeable to ions or to the drug. 18.00 h, and a snack at 21.00 h); for subjects receiving
The objectives of this feasibility study were to the IR treatment at nighttime, snack was not given.
characterize the pharmacokinetics of amitriptyline and its Subjects remained in the clinic 4860 h after the initial
metabolite nortriptyline following OROSA and IR dose, and they were instructed to return to the clinic for
treatments, and to correlate them with the anticholi- the remaining blood draws and measurements.
nergic effects.

Assessments
Methods
Safety Treatment safety assessments included blood
Subjects
pressure and heart rate measurements, which were taken
Fifteen healthy male subjects, 2137 years (mean 29 years), before and at predetermined times throughout the study.
with a mean weight of 77.4 kg (6194 kg), were enrolled In addition, laboratory parameters were assessed before
in the study. and at the end of the study. Adverse events volunteered
This feasibility study protocol was reviewed and by subjects were also recorded.

72 1999 Blackwell Science Ltd Br J Clin Pharmacol, 48, 7178


OROS and immediate release amitriptyline

Anticholinergic effects Saliva output, dry mouth ratings, control samples for amitriptyline and nortriptyline was
and visual acuity following each treatment were assessed <7.0%.
at specific times during the study. The assessment times Model independent methods were used to determine
for saliva output and dry mouth were predose, 1, 2, 4, 6, the following pharmacokinetic parameters for amitripty-
8, 12, 16, 24, 30, 36, 48, 60, 72 and 84 h post dosing. line and nortriptyline: the maximum observed plasma
Likewise visual acuity test was done at predose, 8 and concentrations (Cmax ) and the corresponding sampling
16 h post dosing. Drowsiness ratings were obtained only time (tmax ), the terminal or disposition rate constant (lz ),
for the OROSA (amitriptyline hydrochloride) and the and the terminal or disposition half-life (t1/2 ). The area
IR every 8 h treatments. Because the IR nighttime under the curve to the last sample collection point
treatment involved frequent awakenings for blood sample (AUC(0,t)) was computed using the linear trapezoidal rule,
collection after dosing, drowsiness ratings were not and the AUC value extrapolated to infinity (AUC(0,00))
solicited in this group. was determined as the sum of AUC(0,t) plus the area
At specific times during the study, the subjects rated extrapolated to infinity, calculated by the concentration
their dry mouth sensation on a 100 mm Visual Analogue at time t (Ct) divided by lz. In addition the relative
Scale (VAS) (0=normally moist; 100=extremely dry). bioavailability ( F) of OROS (amitriptyline hydrochloride)
Dry mouth assessments were done before the saliva was also computed using the IR every 8 h as the reference
output test. treatment.
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 Pharmacodynamics
test. A drop of 1% citric acid was placed on his tongue; For each treatment, plasma concentration and anticholi-
he was instructed not to swallow for 2 min and then to nergic effects across all subjects were averaged at each
spit the saliva into a clean, dry, preweighed beaker. sample collection time. The means of selected anticholi-
The sedation ratings were done at specific times during nergic effects (decreased saliva production, drowsiness,
the study, and the subjects gave their subjective assessments and dry mouth) were correlated to plasma amitriptyline
of drowsiness using a 100 mm VAS (0=extremely alert; and nortriptyline concentrations. The data were fitted to
100=extremely drowsy). Subjects who fell asleep during the sigmoidal Hill equation using the nonlinear regression
the 06.00 h22.00 h period were given the maximal method in SAS:
score (100) for that period. EmaxCt
c

Visual function was assessed before dosing and at 8 and Et=E0


C50+Ct
c c
16 h after the dose; near and far vision were evaluated
using the near vision card and the Snellen eye chart, where:
respectively.
Et=value (weight or rating ) of the observed effect at
Pharmacokinetics methods time t
Following dosing of each treatment, serial blood samples E0=baseline value (weight or rating)
for pharmacokinetic evaluation of amitriptyline and
nortriptyline were collected immediately before dosing EC50=plasma drug concentration required to produce
and for a period of 84 h after administration of the dose. 50% of the maximum effect
The plasma samples were analysed for determination Emax=maximum effect (weight or rating) observed
of amitriptyline and nortriptyline using a gas chromatogra-
phy method. Amitriptyline, nortriptyline, and an internal Ct=plasma drug concentration at time t
standard, desipramine, were extracted from the alkaline c=Hill coefficient
plasma into a hexanol/butanol mixture. The hexanol/
butanol phase was then back-extracted with hydrochloric An alternative method for correlating drug concentration
acid. The acid phase was made alkaline, followed by with anticholinergic effects was pursued by normalizing
extraction with butyl acetate. Analysis was done by gas (linear transformationz score) the anticholinergic effects
chromatography with nitrogen phosphorous detection. toward the mean value and correlating this with plasma
This method was validated with a minimum quantifi- amitriptyline concentration. The advantage of transform-
able concentration of 0.5 ng ml1 for amitriptyline and ation to z score is it enables comparison of plasma
nortriptyline. The samples were kept frozen at 20 C concentration and different measures of the anticholi-
before analysis, and a 1ml sample was used for analysis. nergic effects in the same domain. The slopes of plots
The day to day variability in measurements of quality were compared to evaluate which anticholinergic effect

1999 Blackwell Science Ltd Br J Clin Pharmacol, 48, 7178 73


S. K. Gupta et al.

correlated best to the plasma concentration. The effects increased slowly, with a mean maximum concentration
were normalized as below: 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
Enor=(EobsEmean )/Esd 1
mean AUC(0, 2) was 593 ng ml h. Similarly,
where: following the nighttime dosing the mean maximum
amitriptyline concentration was 26.8 ng ml1, and the
Enor=normalized (around mean) effect
corresponding AUC(0, 2) was 688 ng ml1 h. The
Eobs=observed effect relative amitriptyline bioavailability with OROSA (ami-
triptyline hydrochloride) compared with IR nighttime
Emean=mean of Eobs
and IR every 8 h treatments were 89% (90% CI
Esd=standard deviation (s.d.) of Eobs 77%102%) and 95% (90% CI 82%108%), respectively.
The plasma nortriptyline concentrations exhibited a
similar pattern to the parent drug amitriptyline after the
Statistics
three treatments, with maximal nortriptyline concen-
1
Phamacokinetic parameters for the three treatments were tration of 12 ng ml occurring after the IR nighttime
compared using an analysis of variance model (anova) treatment and the most delayed tmax of 34.6 h observed
appropriate for a crossover study design. The statistical with OROSA (amitriptyline hydrochloride) treatment
computer package PCSAS version 6.10 (SAS Institute, (Table 2 and Figure 2). The mean apparent elimination
NC, USA) was used for statistical analysis. The variance half-life values for nortriptyline were similar among all
model included terms for treatment, subject within three treatments and ranged from 33 to 44 h. The mean
sequence, treatment sequence, and period. 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-
Results
chloride) treatment.
Pharmacokinetics The mean metabolite-to-drug AUC(0, 2) values for
the OROSA (amitriptyline hydrochloride), IR every 8 h,
Baseline measurements were completed for 15 subjects.
and IR nighttime treatments were 0.91, 1.02, and 1.0,
One subject was withdrawn from the study before
respectively, and were not significantly different from
receiving any study medication because he admitted that
each other ( P=0.37). Therefore, the extent of formation
he was a smoker. The baseline value for this subject was
and elimination of nortriptyline was similar after each of
excluded from analysis. The remaining 14 subjects
the three treatments.
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-
Anticholinergic effects
line concentrations increased rapidly after the second
hour of each of the first two doses and a mean maximum The mean ratings for dry mouth during the IR every
concentration of 19 ng ml1 occurred about 6 h after 8 h and OROSA (amitriptyline hydrochloride) treatments
dosing. The mean half-life value for amitriptyline were not significantly different from baseline or from
following the every 8 h treatment was 19.4 h and the each other. However, the mean ratings during the IR
1
corresponding AUC(0, 2) was 661 ng ml h. nighttime treatment were significantly higher than those
Following the OROSA (amitriptyline hydrochloride) associated with the other two treatments and the mean
administration, the plasma amitriptyline concentrations 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 were significantly increased from baseline at the 8 h
during OROSA (amitriptyline hydrochloride) and IR measurement.
every 8 h treatments were not significantly different from A minor, clinically insignificant decrease in visual
each other or from the mean baseline values for most acuity was observed after each of the three treatments as
periods analysed. During IR nighttime treatment, the compared with baseline values. Seven subjects during
mean amount of saliva produced was significantly less OROSA (amitriptyline hydrochloride) and IR every 8 h
than at baseline or during the other two treatments for treatments and five subjects during the IR nighttime
most periods. The mean weight of saliva produced was treatments experienced this effect.
observed to be the lowest following the IR nighttime
dosing with a drop of 65% from baseline at 8 h after
Concentration-effect relationship
dosing, which was sustained for about 16 h after dosing
when it was still only 50% of the baseline observation. After the IR nighttime dosing, the peripheral anticholi-
The mean drowsiness values for the OROSA (amitrip- nergic effect (saliva production) was most reduced (65%)
tyline hydrochloride) and the IR every 8 h treatments from baseline at the 8 h measurement when the amitripty-
1
were not significantly different from each other but 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 20 Discussion
Plasma amitriptyline concentration (ngml1)
The sustained-release characteristic of OROSA (amitrip-
Figure 3 Predicted and mean observed plasma amitriptyline
concentrations and anticholinergic effects following the three
tyline hydrochloride) was confirmed by the relatively flat
study treatments: OROSA (#, amitriptyline hydrochloride), plasma concentration of amitriptyline for 36 h after
immediate release every 8 h (6, IR every 8 h) and immediate dosing. The absorption of amitriptyline was not only
release at nighttime ($, IR HS). sustained but also delayed, with undetectable amitriptyline
concentrations for 46 h after dosing, which was attri-
highest and least correlating compared with that of the buted to the slow release characteristics of amitriptyline
other two effects (Figure 4). The range of amitriptyline from OROSA. A similar pattern was also observed for
concentration for drowsiness comparison was too narrow nortriptyline. After IR nighttime dosing, the mean plasma
compared with that of other anticholinergic effects, to amitriptyline concentration increased rapidly, peaked at
establish a reasonable concentration-effect relationship. In 6 h (27 ng ml1 ), and was maintained consistently higher
contrast, the dry mouth and saliva weight effects correlated compared with the other treatments for a period of
well with plasma drug concentration and seemed to be 1624 h. Minimal change in the drug to metabolite ratio
similarly sensitive to changes in drug concentration. 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 incidence of adverse effects are possible benefits of
following IR administration, however, due to the OROSA formulation.
extended release characteristics of OROSA it seems the In conclusion, based on this feasibility study the relative
extent of metabolism is independent of the site of release bioavailability of OROSA (amitriptyline hydrochloride)
of the drug from the formulation, thereby resulting in was similar to the two IR treatments and nortriptyline
similar drug to metabolite ratio. However, the three formation also appeared to be similar amongst the
treatments results in very different concentration effect treatments. Some of the anticholinergic side-effects seem
time profiles, this could be due to the sensitivity of these to be concentration-related so those side-effects may be
anticholinergic effects to the drug concentration in the reduced with a controlled release formulation. However,
body. The peripheral anticholinergic effect (decreased these conclusions are based on a study in a small group
saliva production) was greatest after the IR nighttime of healthy volunteers; the true clinical benefits of a
dosing, with a 65% drop from baseline in mean saliva controlled release dosage formulation need to be demon-
production at 8 h after dosing, when the plasma amitripty- strated in patients.
1
line concentration was about 25 ng ml . This effect
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78 1999 Blackwell Science Ltd Br J Clin Pharmacol, 48, 7178