Pharmacokinetic Evaluation of a Sustained-Release
Formulation of Trihexyphenidyl in Healthy Volunteers
WING K. CHEUNG, STEVEN s. STRAVlNSKl, STEVEN I. ENGEL,LUISAL. SIA, AVRAHAMYACOBI,
AND SILBER’
6. MICHAEL
Received January 19, 1988, from the Medical Research Division and Lederle Laboratories, American Cyanamid Company,
Pearl River, NY 10965. Accepted for publication April 26, 1988.
Abstract 0 Twenty-four male subjects were randomizedto receive two
oral dosage forms of trihexyphenidyl HCI (a-cyclohexyl-a-phenyl-l-
piperidinepropanol HCI). The dosage regimens were (7) a 5-mg immedi-
ate release (IR) tablet given twice daily at time zero and 12 h later, and
(2)two 5-mg sustained-release(SR) capsule formulations given daily.
The number of adverse experiences following the SR formulation were
-50% of those for the IR formulation, the peak concentration (C,,)
after the SR formulationwas significantly lower (p < 0.05)than that after
the first dose of the IR formulation, and the time to reach C,, (La)was
significantly longer after the SR formulation (p < 0.05). The SR
formulation maintained serum concentrations above 50,60,and 70% of
,,C values for average time periods of 11.7,9.4, and 5.9 h, respective-
ly, compared with values of 1.8, 1.2, and 0.9 h after the IR formulation;
the differences were all significant (p < 0.05).The mean elimination half-
life (ti,*) was similar (p > 0.05)after the SR (10.1 h) and IR (8.7 h)
formulations. The statistical power of the study was 98.1% to detect a
20% difference in the area under the curve from time zero to time infinity
(AUCb,) between formulations. Although the AUC-, after the SR
formulation was statistically smaller (p < 0.05) than after the IR tablet,
the difference was <20%. Therefore, the SR formulation was bioequiva-
lent to the IR tablet formulation of trihexyphenidyl.
Controlled-release (CR) or sustained-release (SR) formula-
tions are used to maintain relatively constant drug concen-
trations in plasma, serum, or blood during a dosing interval
(7).This type of formulation can often result in a lower
incidence of drug toxicity, by reducing peak serum concentra-
tions, and also increase the period over which concentrations
can be maintained above the minimum effective concentra-
tion, by reducing the peak (C,,,)-to-trough (Cmin)concentra-
tion ratios (C,,:C,in).
It would be desirable to have some objective numerical
criterion to assess the in vivo performance of CR or SR
formulations. Jackson et a1.l compared two SR formulations
of theophylline by comparing the fluctuation ratio, which
was defined as the quotient obtained from (C,, - Cmin)/
C,,,). Hendeles et a1.2evaluated different SR formulations of
theophylline using another percentage fluctuation method
which was defined as the ratio of (Cmax - CrninY(Cmin).
Neither of these fluctuation ratio values can objectively shed
light on the performance of SR or CR formulations because
they depend on the T values selected. Meier et al.3 proposed
the use of a parameter called the half-value duration (HVD)
as the criterion for evaluating the performance of CR or SR
formulations. The HVD is the duration of time for which
plasma concentrations are above one-half of the observed
C,, value. The HVD value does not depend on the T values
during multiple dosing and can also be obtained from single-
dose studies. However, both HVD and the fluctuation ratio
methods have one important drawback in that they are
insensitive to the shape of the concentration-time profile.
748 /Journal of Pharmaceutical Sciences
Vol. 77, No. 9, September 1988
An ideal SR or CR formulation will maintain constant
plasma concentrations after C,, has been reached. There-
fore, a n optimal way of characterizing the performance of a
SR or CR formulation would be to determine the time
duration over which the plasma concentrations are sustained
above a certain percentage of the C, value. To avoid a
potential misinterpretation of the data because of possible
abrupt changes in plasma concentration-time profiles, a
series of percentages of the C,, value should be used.
In this paper, we use a new method to evaluate the
performance of a SR formulation of trihexyphenidyl hydro-
chloride (a-cyclohexyl-a-phenyl-1-piperidinepropanol HC1)
relative to that of an immediate-release formulation. Trihex-
yphenidyl is a synthetic antispasmodic drug that is widely
used in the treatment of patients with all forms of parkinson-
ism, including primary or idiopathic Parkinson’s disease, as
well as those with secondary symptomatic parkinsonism
(postencephalitic, arteriosclerotic, infection-induced, tumor-
induced, trauma-induced, and drug-induced). The method of
analysis used achieves two objectives: It allows an evaluation
of the performance of CR or SR formulations independent of T
and it takes into account the shape of the concentration-time
profile.
Experimental Section
Subjects-Wenty-four healthy male subjects, ranging in age
from 20 to 33 years (24.4t 3.4years; mean +. SD), ranging in weight
from 55.9 to 86.4kg (74.62 8.0 kg), and ranging in height from 65 to
74 cm (70.5 +. 2.6cm), were enrolled in the study after giving written
informed consent in accordance with the research review and ethics
committee a t Bio-Research Laboratories, Montreal, Quebec, Canada.
The subjects were confirmed to be in good health by physical
examination, medical history, and clinical laboratory tests. They had
no concurrent illness, had no history of allergy or adverse reactions
to other medications, were not on chronic prescription or over-the-
counter drug therapy, had no history of alcoholism, drug abuse,
psychosis, poor motivation, or emotional or intellectual problems
that were likely to limit the validity of informed consent, and had not
participated in another investigational drug research study within
the previous 30 d.
Study Design-This was a randomized, two-way crossover study
comparing two oral dosage forms of trihexyphenidyl hydrochloride
(a-cyclohexyl-a-phenyl-1-piperidinepropanol HCI): a 5-mg sus-
tained-release (SR)capsule (Sequel; lot no. 4438-316,Lederle Labo-
ratories) and a 5-mg conventional immediate release (IR)tablet
(Artane; lot no. 4436-804,Lederle Laboratories). Subjects were
assigned numbers sequentially as they entered the study and were
confined to the clinical study facility on study days 1, 2,9, and 10.
Adverse experiences were monitored throughout the study by asking
“How do you feel?” at 1,4,8,12,13, 16,and 24 h after each dose of
the drug. For each adverse experience episode noted, the investigator
recorded the onset, duration, and intensity (mild, moderate, or
severe), together with the actions taken for the adverse experience
and the subject’s outcome. Additional adverse experiences were
0022-3549/88/0900-0748$0 1.0010
0 1988, American Pharmaceutical Association
monitored by laboratory tests of hematopoietic, renal, and hepatobi-
liary functions that were performed within 24 h prior to dosing on
day 1and on day 10 at the completion of the study. The subjects were
randomly divided into two groups. One group received a 5-mg IR
tablet at time zero and another 5-mg tablet 12 h later on day 1.
Following a 9-d washout period, each subject received two 5-mg SR
capsules administered at time zero. The sequence of treatment for
the other group was reversed. All subjects ingested the formulation
with 250 mL of tap water. Breakfast (juice, milk, corn flakes, and
toast) was ingested 2 h before the morning dose in both phases.
Dinner (a standard meal) was also served 10 h after the morning
dose in both phases. Each subject reported to the live-in facilities at
Bio-Research Laboratories (Senneville, Quebec) by 8:OO p.m. the
evening before drug administration (days 1and 91, and stayed in the
facilities until 4 to 6 h after the last blood drawing. Blood samples
were drawn at time zero (pre-dose) and 0.5, 1, 1.5, 2, 2.5,4,6, 8, 10,
12,12.5,13,13.5,14,14.5,16,18,20,24,27,30,36,42,and48 h after
the beginning of dosing on days 1 and 9. The harvested sera were
stored frozen (-20 "C) until assayed.
Assay-Concentrations of trihexyphenidyl in serum were assayed
by a validated high-resolution gas chromatographic method using a
nitrogen detector.4 Linearity of this assay method was observed over
the concentration range of 1 to 150 ngImL, with coefficients of
variation ranging from 4.2 to 10.5%.
Data Analysis-In the present study, the time durations wherein
plasma concentrations were sustained above 70 (D7& 60 (Dso),and
50% (O5Jof the respective C, values were determined. Pharmaco-
kinetic parameters were determined using model-independent meth-
ods.6 The area under the serum concentration-time curve (AUC)
from time zero to the last time point (AUC-,, where t is the time of
the last reportable drug concentration) was determined by the
trapezoidal rule. On descending concentrations, AUC values be-
tween time points were determined with the log-linear trapezoidal
method; otherwise, the linear trapezoidal method was used. The
AUC values from time zero to time infinity (AUC-,) were deter-
mined by adding to AUC-, the quotient of CJK, where C,is the
serum concentration at time t , and K is the elimination rate constant
which was determined from the slope of the terminal log-linear
portion of the serum concentration-time curve using the method of
least-squares regression. The terminal half-life (tlla)was determined
as the quotient of In 2 divided by K. The C,, for the first dose of the
IR tablet or for the SR capsule CC-,I, C,, for the second dose of the
IR tablet (CmUz),and the time to Cml (t-) were determined by
visual inspection of the serum concentration-time curve. The adjust-
ed t,, for the SR formulation and the first dose of the IR tablet
formulation were determined by subtracting from t- the corre-
sponding lag time (tlag), where tlae is equal to the time period from
time zero to the trw over which the serum concentrations were not
measurable or reportable (below the assay quantitation limit). The
oral clearance (CL,), which is equal to the ratio of CLIF, where CL
and F are the systemic clearance and absolute bioavailability,
respectively, was determined by the ratio of the oral dose and the
AUC,,.
Statistical Analysis-Analysis of variance (ANOVA) was used in
the statistical analysis of the pbrmacokinetic parameters. The
linear model included formulation, period, and subject as factors.
Results
Clinical Findings-Many of the subjects experienced the
expected mild, drug-related clinical adverse reactions, but
overall, the two formulations were well tolerated. The most
frequently occurring side effects for the two formulations
included dizziness, lethargyltiredness, lightheadedness, and
headache. On a cumulative basis, there were -50% fewer
drug-related side effects observed after the SR capsule formu-
lation than after the IR tablets (Table I).
Pharmacokinetic Analysis-Mean serum concentration-
time profiles of the drug following each formulation are
shown in Figure 1. The pharmacokinetic parameters for
trihexyphenidyl in subjects after receiving the IR tablet or
the SR formulation are listed in Table 11. The 1 C, for the
SR formulation was significantly lower (p < 0.05) than that
for the IR tablet, and the tmaxfor the SR formulation, after
adjusting for tlag, was significantly longer for the SR formula-
tion (p < 0.05). There were no significant differences in K, t,,,,
or CL, between the two formulations (p > 0.05). Although
the AUC&, value after the SR formulation was significant-
ly smaller than that after the IR tablet (p = 0.021, the
difference was <20% of the IR tablet mean value (difference
= -11.8%, the two one-sided 95% confidence limits were
-19.8% and -3.9%). The statistical power of the study was
98.1%to detect a 20% difference in AUC&, values between
the two formulations. Therefore, the SR formulation of tri-
hexyphenidyl was bioequivalent to the IR tablet formulation.
The sequence of dosing had no effect on the pharmacokinetics
of trihexyphenidyl.
Evaluation of Sustained-Release CharacteristicoThe
values of D70, DG0,and Ds0 after the first dose of the IR
formulation and after the SR formulation are listed in Table
11. There were no large fluctuations in serum concentrations
after the SR formulation (Figure 1). This formulation of
trihexyphenidyl was able to sustain serum concentrations of
the drug above 70,60,and 50%of the achieved, ,C values
for average time periods of 5.9, 9.4, and 11.7 h, respectively,
compared with mean time periods of only 0.9, 1.2, and 1.8h,
respectively, for the IR tablet. These differences were all
significant (p < 0.05).
Discussion
The performance characteristics of a SR formulation of
trihexyphenidyl were characterized in this study by D70, DSO,
and Ds0 values. The corresponding values determined after
the first dose of the IR tablet formulation were substantially
smaller than those observed following the SR formulation (p
< 0.05; Table 11).Therefore, there was a clear indication that
the SR formulation of the drug had good SR characteristics.
Perhaps of greater importance clinically, the number of
adverse experiences following the SR formulation was only
-50% of that observed following the IR formulation of the
drug (Table I).
There was a lag time in the absorption of the drug in some
of the subjects receiving the IR tablet formulation and in all
subjects receiving the SR formulation (Figure 11, suggesting
that there might have been a small delay in gastric emptying
or a delay in the release of drug from the dosage form. The
tlagfor the SR formulation was significantly longer (p < 0.05)
than that for the first dose of the IR tablet. The tlag for the
second dose of the IR tablet was not possible to assess since
there were residual concentrations from the first IR tablet
dose.
In a previous clinical study (unpublished data), only four
out of 24 subjects who received the IR tablet formulation had
tiag values up to 0.25 h, whereas 13out of the 24 subjects who
received the IR tablet in this study had tlag values ranging
from 0.5 to 1 h. In that previous study, food was ingested 4 h
after drug administration. In contrast, breakfast (juice, milk,
corn flakes, and toast) was ingested 2 h before drug adminis-
tration in the present study. Therefore, it appears that food
caused a small (0.4 h) delay in.drug absorption, possibly by
delaying gastric emptying. In addition, the C, for the
second dose of the IR tablet, instead of being higher than that
of the first dose (since there was residual drug concentrations
from the first IR tablet), was significantly lower than the
C,, for the first dose (p < 0.01). The second IR tablet dose
was administered 2 h after dinner (standard meals, identical
for both periods), which was a more substantial meal than
breakfast (served 2 h before the first dose of the IR tablet).
This suggests that food may have a smqll effect on the
absorption kinetics of trihexyphenidyl given as an IR tablet.
In summary, the SR formulation of trihexyphenidyl had
good SR characteristics and was bioequivalent to the conven-
Journal of Pharmaceutical Sciences / 749
Vol. 77, No. 9, September 1988
Table I-Summary of Adverse Experiences following Doses of Trlhexyphenidyl by Type and Incidence
IR Tablet ~ SR Capsulea
Mild Moderate Mild
Side Effect
No. Of Total No. Of Total No. Of Total
Episodes Duration, h Episodes Duration, h Episodes Duration, h
Dizziness 18 105 1 9 12 121
Lethargyltiredness 7 38 3 35
Lightheadedness 9 58 3 34
Headache 3 28 2 19 3 21
Blurred vision 2 13 2 19
Cold/clammy hands 3 46 1 15
Nausea 3 70
Twitchingkhaking 1 1 min 2 47
Euphoria 2 28
Disorientationllackof concentration 2 12
Lack of coordination 2 13
Heart palpitation 0 0 2 min
Weakness 1 2 1 min
Heaviness-leg/arm 1 9 11
Chest pain 1 7 1 min
Heavy perspiration 1 4 3
Tingling fingers 0 0 4
Sweaty palms 0 0 4
Soreness abdomenlstomach 2 108
Cold feeling-arm 1 0.5
Strange taste 1 6
Warm feeling 0 0
Chest muscle spasm 3
Sore thigh 1 41
Whistling right ear 10 min
Upper arm tenderness 1 17
Numbnesslchin 1 60
Sore shoulder 1 13
Visual white spots 2
Pressure base head 6
Diarrhea 13
a No "moderate" side effects were reported after the SR formulation.

Table 11-Pharmacoklnetic Parameters for Trihexyphenidyl in

Healthy Volunteers'
IR SR ANOVA
Parameter
Formulation Formulation p value
AUCc .I, nghlmL 334 f 243 294 2 251 0.02
4ag3 hb 0.4 t 0.4 0.7 f 0.5 <0.05
L a x , hb 2.0 f 0.8 3.7 rt 2.2 <0.05
tmax - tlags hb
Cmaxl, nglmLb
1.6 t 0.7
30.8 t 15.2
3.0 f 2.0
*
14.9 7.6
<0.05
<0.05
YI o &'1
w '1 -
,-. , - \-*- -
?

Cmaxp, ng/mLc 24.4 f 12.0 - d -d 0 4 812162024283236404440

TIME, noun
C L , Uh 42.6 t 23.4 47.7 -1- 21.2 >0.05
K, h-' 0.0918 f 0.0363 0.0774 t 0.0247 >0.05 Figure 1- Mean serum concentrations of trihexyphenidyl in healthy
1 ,h 8.67 f 3.23 10.1 ? 4.3 >0.05 volunteers after receiving two 5-mg immediate-releasetablets adminis-
$0, h 1.8 t 1.1 11.7 f 2.5 C0.05 tered 12 h apart (square) or as two 5-mg sustained-release capsules
&or h 1.2 t 0.8 9.4 f 3.6 C0.05 administeredat time zero (circle).
4 0 ,h 0.9 t 0.6 5.9 t 4.0 c0.05
plicability to the evaluation o f SR formulations for other
a Determined after subjects received 10-mg doses administered as drugs and illustrates h o w SR formulations can potentially
either two 5-mg immediate-release(IR) tablets given 12 h apart, or as a improve the safe utilization o f drugs, especially those that
single dose of two 5-mg sustained-release (SR) capsules. bValues
can produce adverse effects related t o the central nervous
presented represent those obtained after the first dose of the IR tablet.
'Values presented represent those obtained after the second dose of system.
the IR tablet. dNot applicable. References and Notes
tional IR tablet formulation o f the drug. The results also 1. Jackson, S.H. D.; Shah, K.; Turner, P. Eur. J.Clin. Pharmacol.
showed that there were n o differences between the disposi- 1986,30,313-317.
2. Hendeles, L.;Weinberger, M. J . Allergy Clin. Zmmunol. 1986,
t i o n kinetics of trihexyphenidyl given as either formulation. 78,743-751.
Furthermore, the use of the SR formulation of the drug 3. Meier, J.;Nuesch, E.; Schmidt, R. Eur. J . Clin.Pharmacol. 1974,
resulted in a substantial reduction in reported adverse ef- 7. 429-432.
I ~~~ ~~

fects, attributable t o a reduction in t h e C,,, observed. 4. Look, Z. M,; Tynan, K. P.; Hoyt, K . D.; Yacobi, A.; Kelly, R. G.J.
Pharm. SCL.1985,15, 144.
The new method described herein for the evaluation o f a 5. Gibaldi, M.; Perrier, D. Pharmacokinetics, 2nd Ed.; Marcel
SR formulation o f trihexyphenidyl should have genera1 ap- Dekker: New York, 1982; pp 409-416.

750 / Journal of PharmaceuticalSciences

Vol. 77, No. 9, September 1988