Pharmacokinetics of transdermally

delivered clonidine
We detail a series of pharmacokinetic investigations to determine the dose linearity, the effect of site of
application, the duration of steady-state plasma concentrations, and the effect of chronic application when
clonidine is administered transdermally. Dose linearity was assessed in six subjects with normotension
after application of increasing sizes of transdermal donidine systems (3.5, 7.0, and 10.5 cm2 size) to the
upper outer arm. Of the six subjects studied, five had linear relationships between donidine plasma
concentrations at steady state and system size of >0.975; in the sixth subject the correlation was >0.90.
The mean steady-state plasma concentrations with 3.5, 7.0, and 10.5 cm' systems were 0.39, 0.84, and
i.12 ng/ml, respectively. The influence of site and duration of application on the absorption of transdermal
donidine was studied in eight subjects with normotension by use of the 3.5 cm' system. The mean steady-
state plasma concentration over the time interval from 3 to 7 days after application to the arm or to the
chest did not significantly differ. When a system was left on the chest or arm for a total of 11 days (4
days beyond the recommended time to change systems), the plasma concentrations of seven of eight
subjects with application to the arm and of six of eight subjects with application to the chest remained
constant through day 11. The influence of consecutive applications of 3.5 cm' transdermal donidine
systems on steady-state plasma clonidine concentrations was also studied in eight subjects with
normotension over an 11-day period. Steady-state plasma concentrations were achieved in all eight subjects
within 3 days after application of the initial transdermal clonidine system. On days 4 and 7 the previous
transdermal system was removed and a new system was applied to the alternate arm. The mean steady-
state plasma concentration (3 to 11 days) for the eight subjects was 0.32 ng/ml. There was no apparent
difference between the mean plasma concentration at the time the donidine system was removed and 24
hours after application of a new system. (CLIN PHARMACOL THER 38:278-284, 1985.)

Thomas R. MacGregor, M.Sc., Kandace M. Matzek, M.Sc., James J. Keirns, Ph.D.,

Rudolf G. A. van Wayjen, M.D., Abraham van den Ende, Ph.D., and
Rudolf G. L. van Tol, Ph.D. Ridgefield, Conn., and Amsterdam and Alkmaar, The Netherlands

Clonidine (Catapres; Boehringer Ingelheim) is an ef-
fective drug in the treatment of mild to moderate hy-
pertension when used alone,6.10 in combination with a
diuretic,' and as a transdermal delivery system (Ca-
tapres-TTS).2.8'11'12 The transdermal system has been
developed to deliver clonidine at a constant rate for 7
days for once-a-week therapy. In cases in which lack
of compliance with oral antihypertensive therapy is an
obstacle to adequate blood pressure control, a 7-day
transdermal system is advantageous in maintaining pre-
dictable, therapeutic blood concentrations.
From Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield; Ver-
eeniging voor Ziekenverpleging and Slotervaart Hospital, Am-
sterdam; and Boehringer Ingelheim b.v., Alkmaar.
Received for publication Feb. 7, 1985; accepted May 1, 1985.
Reprint requests to: Thomas R. MacGregor, M.Sc., Research and
Development, Boehringer Ingelheim, P.O. Box 368, Ridgefield,
CT 06877.
278
Clonidine is a lipid-soluble, relatively potent drug
with a high volume of distribution and a therapeutically
effective low plasma concentration.2 These properties
permit clonidine to be incorporated into a 7-day trans-
dermal delivery device. The clonidine transdermal de-
livery system is a tan-colored square unit with rounded
edges composed of a flexible system of membranes that
adheres to the skin. The development of a specific and
sensitive RIA for plasma clonidine determinations' .2 has
facilitated the exploration of the pharmacokinetic prop-
erties of the drug.
We describe a series of pharmacokinetic studies un-
dertaken to determine the dose linearity of three dif-
ferent-sized systems, the effect of anatomic site of ap-
plication, the duration of plasma clonidine steady-state
concentrations when the system is not removed after 7
days, and the effect of chronic application of the system
on clonidine steady-state plasma concentrations.
VOLUME 38
NUMBER 3 Transdermal clonidine kinetics 279

SUBJECT 1 SUBJECT 2
1.50 1.50 5951e111 System
Applied Removed

25 1.25

I 00

2 2
0.75 0.75

U 0.50 0 50

8
0.25 0.25

0.00 0.00
4 5 6 3 4 5 6 7 10
TIME (days) TIME (days)

SUBJECT 3 SUBJECT 4
1.50 System System
Applied Roll sled

1.25

0 75

8
0.25

2 3 4 5 6 7 8
TIME (days)

SUBJECT 5 SUBJECT 6
1.50 System System
Applied Removed

1 25

0.25

2 3 4 5 6 7 8 9 10
TIME (days)

Fig. 1. Clonidine plasma concentrations from the 3.5 (0), 7.0 (Gi), and 10.5 (0) cm' systems
worn over a 7-day period in six subjects. There is a y-axis change in subject 3.

METHODS Exclusion criteria were women, recognizable medi-

Our subjects were men between the ages of 18 and
45 years who had normal weight. All subjects were in
good health as documented by history and physical
examinations, including chest x-ray, ECG, hematology,
clinical chemistry, and urinalysis.
Blood and urine samples for laboratory examination
were collected in the morning before the start of and
at the end of each study after a 10-hour fast. If labo-
ratory parameters at the end of each study were not
within the normal range, laboratory examinations were
repeated within 24 hours.
cal problems (cardiovascular, hepatic, renal, hemato-
logic, or other organ abnormality or pathology), skin
disease of any type or a history of skin allergies, con-
comitant medications, blood pressure measured on 2
days (both sitting and standing) of >140/90 mm Hg or
<110/70 mm Hg, a resting pulse rate <55 bpm, or
suspicion of sinus node dysfunction.
Before application of the transdermal delivery system
to a nonhairy area of intact skin, the site of application
was cleaned with ethanol. Sites showing any abrasion
or irritation were avoided. An overlay adhesive was
 CL1N PHARMACOL THER
280 MacGregor et al. SEPTEMBER 1985

Table I. Compilation of pharmacokinetic parameters for transdermally delivered clonidine over three sizes of
systems for 7 days of wear
Urine Percent
Size of excretion Renal load 131*
Subject system rate clearance released* tlIzt (nglmll
No. (cm2) (nglml) (p,g1hr) (LIhr) (%) (hr) 3.5 cm2) (nglml)

1 3.5 0.298 2.60 8.72 25.2 14

7.0 0.791 5.07 6.41 48.8 21
10.5 0.680 4.36 6.41 40.3 18 0.253 +0.062 0.90
2 3.5 0.341 3.58 10.50 49.6 14
7.0 0.766 8.73 10.34 56.2 16
10.5 1.145 13.07 11.41 48.1 19 0.386 0.016 0.99
3 3.5 0.631 4.68 7.42 82.8 15
7.0 1.404 8.73 6.22 77.2 17
10.5 2.200 17.93 8.15 81.3 17 0.737 0.047 0.99
4 3.5 0.255 2.13 8.35 48.4 17
7.0 0.461 2.40 5.21 38.0 26
10.5 0.830 5.22 6.29 30.0 26 0.270 0.018 0.99
5 3.5 0.366 2.26 6.17 39.6 18
7.0 0.858 6.64 7.74 50.4 24
10.5 0.965 4.39 4.55 57.3 20 0.339 +0.039 0.98
6 3.5 0.431 1.58 3.67 42.0 20
7.0 0.733 1.81 2.47 32.0 20
10.5 0.891 1.41 1.58 48.8 18 0.298 +0.068 0.98
C" -=- Steady-state plasma concentration; 13, -= slope; 13° = intercept; r = correlation coefficient.
*Calculated after residual analysis.
I-Value is the tr2 of decline after removal of the system.
Minear equation and correlation of the steady-state values obtained; = 13, (n 3.5 cm2) + 13,

used. The transdermal system and overlay adhesive
were applied and removed by the investigator. Because
the clonidine delivery system has an occlusive backing
membrane, the overlay adhesive would not be expected
to alter either drug delivery or skin hydration properties.
There were no dietary restrictions during the study, but
subjects were asked to discontinue alcoholic beverages
24 hours before and during the study. Smoking behavior
of the subjects was recorded.
At specified times throughout each of the studies (0,
24, 48, 72, 76, 80, 84, 96, 120, 144, 168, 172, 176,
180, 192, 216, and 240 hours for the dose linearity
study; additional samples at 264 and 288 hours for the
anatomic placement and duration studies; and at 0, 24,
48, 72, 96, 100, 104, 108, 120, 144, 168, 172, 176,
180, 192, 216, 240, 264, 268, and 272 hours for the
consecutive application study), venous blood samples
(5 ml) were drawn from the median cubital vein in
plastic syringes and collected in heparinized tubes. The
tubes were inverted twice with foil on top and centri-
fuged at approximately 300 x g for 3 minutes. The
plasma was transferred to plastic tubes that were stored
frozen at approximately 20° C until analysis by RIA.
For the dose linearity assessment, a series of three
systems were used on the upper outer right arm. Sys-
tems of 3.5, 7.0, and 10.5 cm2 were applied for 7 days
and then removed. Clonidine plasma concentrations
were measured over a 10-day period with a 14-day
washout between applications. Dose linearity was as-
sessed by comparing steady-state plasma concentrations
for the three systems 4, 5, 6, and 7 days after application
of the appropriate sized system. Linear correlations
were assessed by comparing the independent variable
of dose (i.e., size of system =-- 0, 3.5, 7.0, 10.5 cm2)
to the dependent variable of plasma steady-state con-
centrations (mean of the four 8 AM time points at
each dose). Comparisons of linear and quadratic
(dose x dose) correlations were by a standard general
linear models routine.9
For the anatomic site of application assessment, 3.5
cm2 systems were applied to a nonhairy area of either
the arm or the chest. Clonidine plasma concentrations
were measured over a 12-day period with a 14-day
washout between doses. A paired t test at each sampling
point was used to determine a significant difference
between sites. The transdermal systems were not re-
moved until 11 days after application, permitting an
assessment of the duration of drug release beyond
the recommended 7-day application period. Clonidine
plasma concentrations on days 4 to 11 for each subject
VOLUME 38
NUMBER 3
0 0.5 1.0 1.5 2.0
TIME FOLLOWING REMOVAL (days)
Fig. 2. Representative decline in clonidine plasma concentrations after removal of the 3.5 (0),
7.0 (Gi ), and 10.5 (4I1) cm2 systems in subjects 3 and 6. The limit of detection for the assay is
5 x 10-2 ng/ml.
were analyzed by ANOVA. Trends were also evaluated
to determine if the rate of release of clonidine from the
transdermal system was lower after the 7-day recom-
mended application period.
The chronic use and replenishment of spent systems
on steady-state plasma concentrations was assessed by
3.5 cm2 systems on alternate arms. Clonidine plasma
concentrations were measured in eight subjects over a
12-day period, with used systems replaced with fresh
systems on days 4 and 7. Intensive plasma sampling
was performed for the 24 hours after replacement to
determine if constant plasma concentrations of cloni-
dine were maintained.
Clonidine elimination kinetics after transdermal input
were determined from the dose linearity study plasma
data points after removal of the delivery systems (i.e.,
7, 7.2, 7.3, 7.5, 8, 9, and 10 days after application).
Renal clearances were determined by comparing cloni-
dine urinary excretion rates over a 24-hour period at
steady state with plasma steady-state concentrations.
Total doses administered in each study were calculated
by assaying the residual clonidine in the transdermal
systems after the exposure period.
RESULTS
Composite curves for the dose linearity study in six
subjects are shown in Fig. 1. Kinetic parameters and
dose linearity correlations are listed in Table I. Al-
though renal clearance and percent release from the
system varied among individuals, subject parameters
were internally consistent. Of the six subjects studied
for dose linearity, only subject 1 showed a lack of
linearity at the larger system size. The t112 values for
all subjects ranged from 14 to 26 hours, with most
Transdermal clonidine kinetics 281
10'
2.5 3.0 0 0.5 1.0 1.5 2.0 2.5 3.0
TIME FOLLOWING REMOVAL (days)
Table II. Comparison of the percent load released
after 11 days of wear on chest or arm
% Released*
Subject
No. Arm Chest
1 62.7 64.6
2 54.9 78.0
3 51.9 80.2
4 68.8 64.8
5 51.0 49.4
6 75.6 54.4
7 72.6 83.1
8 81.7 87.5
X ± SD 64.9 ± 11.6 70.3 ± 14.0
*Calculated after system residual analysis.
clustered about 17 to 20 hours. The values were ti
calculated from the decline in plasma clonidine con-
centrations after system removal (Fig. 2) and appear to
be dose independent. A comparison of anatomic site of
application with the 3.5 cm2 system reveals no signif-
icant difference between chest and arm (Fig. 3) over
the 7 days recommended for wear. This was consistent
with the percent of load delivered (Table II) estimated
from residual system analysis after removal on day 11.
The 3.5 cm2 systems were left in place for 4 days past
the recommended removal time to determine duration
of release. Although there were no significant differ-
ences among days 7, 8, 9, 10, and 11, there was a
downward trend in mean clonidine plasma concentra-
tions after approximately 9 days of wear. Chronic re-
moval and application of a fresh system was studied at
plasma clonidine steady-state concentrations ( Fig. 4).
 CL1N PHARMACOL THER
282 MacGregor et al. SEPTEMBER 1985

System Recommended
Applied Removal Time System Removed

2 3 4 5 6 7 8 9 10 11 12

TIME FOLLOWING FIRST APPLICATION (days)

Fig. 3. Time course of mean ( ± SE) plasma clonidine concentrations in eight subjects receiving
3.5 cm' systems on the arm or the chest for 11 days (4 days past label-recommended removal).

.5

2 3 4 5 6 7 8 9 10 11 12
TIME FOLLOWING FIRST APPLICATION (days)

Fig. 4. Time course of mean ( SE) clonidine plasma concentrations in eight subjects receiving
consecutive 3.5 cm2 systems at 4 and 7 days. f = Removal; J. = application.

There was no significant difference between clonidine
plasma concentrations at time of replacement and 24
hours later. Most plasma samples assayed for the eight
subjects were in the range of 0.3 to 0.4 ng/ml, as desired
for a 3.5 cm2 transdermal clonidine system.
DISCUSSION
Several factors unique to the pharmacokinetics of a
drug are present when input is by transdermal delivery.
Factors such as site of application, dose titration, extent
of system drug release, and reproducibility of blood
concentrations with chronic application must be fully
investigated and clearly understood. Our series of stud-
ies attempted to evaluate critically transdermally deliv-
ered clonidine as a practical therapeutic alternative to
oral antihypertensive therapy. Oral clonidine has an
effective range in mild to moderate hypertension of 0.3
to 2 ng/m1.4 Clinical studies have shown transdermal
clonidine to be safe and effective in the treatment of
hypertension:7'8'11'12 The dose linearity study gave mean
plasma concentrations of 0.39, 0.84, and 1.12 ng/ml
for the system sizes of 3.5, 7.0, and 10.5 cm2, respec-
tively, thereby covering the therapeutic range reported
for oral clonidine.
Dose linearity was established by examining three
different-sized systems and correlating surface area of
release to the steady-state clonidine plasma concentra-
tions obtained. Within each subject there was approx-
imate linearity, but not all subjects obtained the same
plasma steady-state levels. This is primarily due to in-
terindividual variations in the clearance of the drug and
in the case of subject 3 to a larger overall dose in all
VOLUME 38
NUMBER 3
three systems. Therefore, one can surmise that the skin
has an influence on the amount of drug released. For
therapeutic use the smallest-sized system should be pre-
scribed and eventually titrated up to a larger size if
greater blood pressure reduction is desired.
There was a lack of dose dependency in the t,,, and
renal clearance, which again emphasizes that the trans-
dermal absorption of clonidine is dose linear. There is
no indication from the parameters in Table I of why
there is a lack of linearity in subject 1 at the highest
dose. This lack of high-dose linearity in this particular
subject would not have led to any toxicity problems,
as the curve was concave-downward. In a clinical sit-
uation this apparent nonlinearity would have been man-
ifested by a lack of increased efficacy when titrating
from 7.0 to 10.5 cm2.
The decline from plasma steady-state levels after sys-
tem removal is shown for two subjects in Fig. 2. There
appears to be a slight increase in plasma clonidine con-
centrations after system removal in some subjects, as
illustrated by subject 6, but this skin depot effect lasted
<1 day. The procedure of removing an adhering system
from the skin would be expected to increase blood flow
to that site and increase drug absorption from the skin.
A depot effect can be helpful in system changeover
during chronic use if the burst effect of the new system
is not enough to compensate for the rate of decline in
plasma concentrations from removal of the old system.
No perceivable skin depot was seen in subject 3, giving
further evidence that in this subject the system mem-
brane was the rate-determining step and the skin had
negligible release characteristics.
For chronic therapeutic use in hypertension, various
anatomic sites of application are needed to prevent po-
tential skin irritation. This could be accomplished if a
patient progressively applies systems from left to right
across the arms and chest. In our limited study of eight
subjects there were no significant differences in the
amounts released from a 3.5 cm2 system (Table II) or
the clonidine plasma steady-state concentrations ob-
tained (Fig. 3).
One major question encountered with dosing every
7 days is what would happen if the patient forgot, for
a day or two, to remove the system. In the study de-
picted in Fig. 3, subjects wore the 3.5 cm2 system for
11 days and a decline in mean clonidine plasma con-
centrations was not seen until the tenth day. Of the
eight subjects studied, seven had no perceivable decline
through all 11 days and one subject (subject 7) declined
significantly after day 7. For another subject (subject
8), only the plasma concentrations after application to
the chest dropped after 7 days of wear. Thus it can be
expected in therapeutic use to be a minor problem if
Transdermed clonidine kinetics 283
systems are left on for a day or two past the recom-
mended removal date. As is shown in Table II, there
is still 20% to 40% of the drug left in the system at 11
days. This much load is needed to drive the drug from
the system to the skin at a zero-order rate. Subjects 7
and 8 appeared to have crossed a threshold percent load
remaining, and zero-order release was not maintained.
Treatment of hypertension is a chronic multiyear pro-
cess. It is assumed that once a plasma steady-state level
is reached it will be maintained with subsequent ap-
plication of fresh systems of the same size. This as-
sumption was tested by multiple system changeover at
steady state with intensive sampling to evaluate cloni-
dine plasma concentrations for the following 24 hours
(Fig. 4). There were no substantial increases or de-
creases in clonidine plasma concentrations during this
24-hour period, with rises and falls in plasma concen-
trations of the same magnitude as during studies in
which there was no system changeover (Figs. 1 and 3)
and intense sampling occurring during the day. Eval-
uation of the 8 AM time points for each day showed no
significant differences and all plasma concentrations
were within the range of 0.3 to 0.4 ng/ml, as expected
with a 3.5 cm2 system. Mean residual analysis of sys-
tems removed after 4, 3, and 4 days of wear showed
28.3%, 26.1%, and 28.6% of the load released.
Our pharmacokinetic studies were designed to an-
swer many questions indigenous to the labeling of a
transdermally delivered drug. We have shown that 3.5,
7.0, and 10.5 cm2 clonidine systems deliver drug at a
rate sufficient to produce plasma concentrations in the
established therapeutic range; there are various ana-
tomic sites for placement of the transdermal clonidine
system with chronic use; clonidine is delivered at a
constant rate for at least 7 days as recommended in the
labeling; and during chronic dosing therapeutic cloni-
dine concentrations will be maintained during the 24
hours after system changeover.
We thank Dr. Zacharias for the residual clonidine analysis,
Dr. H. Esber, P. Zavorskas, Dr. P. Farina, and C. Homon
for the plasma clonidine determinations, and K. O'Connor
for helpful technical discussion.
References
Arndts D, Stahle H, Forster HJ: Development of a R1A
for clonidine and its comparison with the reference meth-
ods. J Pharmacol Methods 6:295-307, 1981.
Dollery CR, Davies DS, Draffan GH, Dargie HJ, Dean
CR, Reid JL, Clare RA, Murray S: Clinical pharmacol-
ogy and pharmacokinetics of clonidine. CLIN PHARMACOL
THER 19:11-17, 1976
Farina PR, Homon CA, Chow CT, Keirns JJ, Zavorskas

284 MacGregor et al.
PA, Esber HJ: Solid phase radioimmunoassay for cloni-
dine in human plasma and urine. Ther Drug Monit. (In
press.)
Frisk-Holmberg M, Paalzow L, Wibell L: Relationship
between the cardiovascular effects and steady-state ki-
netics of clonidine in hypertension. Eur J Clin Pharmacol
26:309-313, 1984.
Grossman S, Gunnels JC: Blood pressure response to a
single daily dose of a clonidine-chlorthalidone combi-
nation. J Clin Pharmacol 20:193-196, 1980.
Lowenstein J: Clonidine. Ann Intern Med 92:74-77,
1980.
McMahon FG: Some new aspects of modern CA-
TAPRES ID therapy in the United States. In Bock KD,
editor: CATAPRES8(clonidine): Pathways in the devel-
opment of a pharmaceutical. Aulendorf, FRG, 1983, Ed-
itio Cantor, pp 118-125.
CLIN PHARMACOL THER
SEPTEMBER 1985
Mroczek WJ: Preliminary evaluation of transdermal clo-
nidine administration in hypertensive patients receiving
a diuretic. In Bock KD, editor: CATAPRES® (clonidine):
Pathways in the development of a pharmaceutical.
Aulendorf, FRG, 1983, Editio Cantor, pp 126-132.
SAS Institute Inc: SAS User's Guide: Statistics, 1982
edition. Cary, NC, 1982, SAS Institute Inc, 584.
Thananopavam C, Golub MS, Eggena P, Barrett JD,
Sambhi MP: Clonidine, a centrally acting sympathetic
inhibitor, as monotherapy for mild to moderate hyper-
tension. Am J Cardiol 49:153-158, 1982.
Weber MA, Drayer JIM: Clinical experience with rate-
controlled delivery of antihypertensive therapy by a trans-
dermal system. Am Heart J 108:231-236, 1984.
Weber MA, Drayer JIM, Brewer DD, Lipson JL: Trans-
dermal continuous antihypertensive therapy. Lancet 1:9-
11, 1984.