Vol.2, No.8, 824-831 (2010)
doi:10.4236/health.2010.28124
Copyright © 2010 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
HEALTH
Pharmacokinetic-Pharmacodynamic modeling of the
analgesic effect of bupredermTM, in mice
Min-Hyuk Yun, Seung-Wei Jeong, Chaul-Min Pai, Sun-Ok Kim*
Samyang Pharmaceutical R&D Center, Daejeon, Republic of Korea; *Corresponding Author: sokim@samyang.com
Received 7 March 2010; revised 31 March 2010; accepted 3 April 2010.
ABSTRACT
Purpose: BupredermTM Buprenorphine trans-
dermal delivery system (BTDS) was developed
for the treatment of post-operative and chronic
pains. This study examined the relationship
between the plasma concentration of bupre-
norphine and its analgesic effect (tail flick test)
in order to assess the usefulness of pharma-
cokinetic-pharmacodynamic (PK-PD) modeling
in describing this relationship. Methods: After
patch application, plasma concentrations of bu-
prenorphine in mice were measured for 72
hours with a validated LC/MS/MS system, and
the analgesic effects were assessed by tail flick
test for the period of 24 hours. A modified two-
compartment open model was used to explain
the PK properties of BTDS, and the PD model
was characterized by slow receptor binding.
Results: The peak buprenorphine level in plasma
was achieved at 1-24 h and the effective thera-
peutic drug concentration was maintained for 72
hours. BupredermTM induced prolongation of
tail-flick latency in a dose and time dependent
manner. Maximum analgesic effect was attained
at 3-6 h and was maintained for 24 h after patch
application. Counter-clockwise hysteresis be-
tween the plasma concentration and the anal-
gesic efficacy of BTDS was observed after Bu-
predermTM application, indicating there was a
delay between plasma concentrations and the
effect observed. From the developed PK-PD
model, Kd values (0.69-0.82 nM) that were de-
rived from the pharmacodynamic parameters
(Kon and Koff) are similar to the reported values
(Kd = 0.76 ± 0.14 nM). Good agreement between
the predicted and observed values was noted
for the rate of change in analgesic effect data
(R2 = 0.822, 0.852 and 0.774 for 0.24, 0.8 and 2.4
mg/patch, respectively). Conclusions: The es-
tablished PK- PD model successfully described
the relationship between plasma concentration
of buprenorphine and its analgesic efficacy
measured by the tail flick test. Our model might
be useful in estimation and prediction of onset,
magnitude and time course of concentration
and pharmacological effects of BTDS and will
be useful to simulate PK-PD profiles with clini-
cal regimens.
Keywords: Pharmacokinetic-Pharmacodynamic
Modeling; BupredermTM; Buprenorphine; Transdermal
System; Slow Receptor-Binding Model
1. INTRODUCTION
Buprenorphine (Figure 1) is a synthetic opiate analgesic
with mixed agonist and antagonist properties [1,2]. It is
derived from thebaine and exerts analgesic effects by
high affinity binding to μ-sub-class opiod receptors in
the central nervous system [3]. The drug is used clini-
cally for the relief of both acute and chronic pain [4] and
experimentally for the treatment of opiod dependence [5,
6]. The duration of action is only twice that of morphine
but the analgesic potency is some 50 times greater [7].
After parenteral administration, the terminal phase half-
life is estimated to be 3 to 5 h and the recommended
frequency of dosing every 6 to 8 h [8]. Following oral
dosing, buprenorphine bioavailability has been demon-
strated to be as low as 10-15%, principally due to exten-
sive first pass metabolism in the gastrointestinal mucosa
and liver [9]. Sublingual buprenorphine has been shown
to be an alternative route for drug delivery [4]. All the
currently available delivery approaches for buprenor-
phine rely on repeated administration to maintain the
desired clinical effect over a prolonged period of time.
Recently trasndermal delivery system of buprenor-
phine, Transtec®, was introduced to overcome frequent
administration required for the management of chronic
pain [10]. There is a delay in the onset of the therapeutic
effect due to the rate-controlled slow release. Reaching
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the effective therapeutic concentration more rapidly after
application of a single patch would be helpful to im-
prove poor pain relief in patients as needed. Hence, we
have developed a new transdermal hydrogel patch, Bu-
predermTM, designed for faster onset and to release bu-
prenorphine at a controlled rate over 72 h at dosages of
28, 42, 56 mg (0.24, 0.8 and 2.4 mg/cm2), and its char-
acteristics have been evaluated in vivo [11].
Modeling of the relationship between drug concentra-
tion and efficacy can allow one to determine which
PK-PD dosing parameter best correlates with treatment
outcomes [12]. The use of PK-PD modeling is of par-
ticular importance to optimize drug use by designing
rational dosage forms and dosage regimes in clinical
pharmacology and pharmaceutical industry. In recent
years, important progress has been made in the field of
mechanism-based PK-PD modeling to characterize the
time-course of the intensity of the drug effect in vivo.
The use of mechanism-based PK-PD models has been
shown to provide understanding in the in vivo pharma-
cology of central nervous system active drugs, including
receptor expression and modulation. In addition, this
approach enables the prediction of the pharmacological
response in humans based on pre-clinical data [13]. Al-
though simple PK or PD characteristics of buprenor-
phine have been determined in blood after intravenous
administration [14-17], the relationship between plasma
concentration and its analgesic effects has not fully elu-
cidated in animals. So far there has been no study re-
porting the establishment of a PK-PD modeling of bu-
prenorphine following patch application.
The objective of this study was to examine the rela-
tionship between the plasma concentration of buprenor-
phine and its analgesic effect (tail flick latency) after
single applications of BupredermTM to mice to assess the
usefulness of PK-PD modeling in describing this rela-
tionship. Accurate modeling should enable the prediction
of the PK and PD profiles of buprenorphine with differ-
ent transdermal dosing strategies.
2. MATERIALS AND METHODS
2.1. Materials and Formulation
The 3 dosage forms of BupredermTM (0.24, 0.8, 2.4
mg/c m 2 with a size of 1 × 1 cm2) were prepared by the
transdermal delivery group at Samyang R&D Center
using proprietary hydrogel matrix technology. These
patches were stored at room temperature until use. Bu-
prenorphine hydrochloride (HCl) and naltrindole (inter-
nal standard) were purchased from MacFarlan Smith Ltd.
(UK) and Sigma (U.S.A.), respectively, and stored re-
frigerated and protected from light. All other reagents
were of analytical grade.
HO
NCH2
CH3
C(CH3)
HO
H3CO
O
C
HCl
Figure 1. The chemical structure of buprenorphine hydrochlo-
ride.
2.2. Animals and Treatment Group
Animals in this study were handled in accordance with
the provisions of “the Principles of Laboratory Animal
Care” (NIH publication #85-23, revised in 1985). Male
ICR (Institute of Cancer Research) mice for single dose
pharmacokinetics and analgesic efficacy studies were
supplied by Charles River Laboratories (Orient, Korea).
Animals were allowed to adapt to the environment in the
laboratory for more than 1 week where constant tem-
perature and humidity were maintained. Then, appar-
ently healthy animals were selected based on their gen-
eral condition and used for the experiment. Animals
were allowed free access to food and water. Subjects
were divided into groups of 8~12 animals for the phar-
macokinetics and analgesic studies
2.3. Study Design
The hair on the dorsal area of the mouse was shaved one
day prior to the beginning of the experiment and one
sheet of patch (0.24, 0.8, and 2.4 mg/patch, size: 1 × 1
cm2) was applied to the shaved skin. The doses of Bu-
predermTM to mice (0.24-2.4 mg/patch) were selected
based on body surface area, metabolic rate and analgesic
effect; which were equivalent to 1/17-1/170 of the clini-
cal dose (2.4 mg/cm2, 42 mg/patch). To prevent partial
peeling and to ensure proper contact with the skin, the
patch was affixed using adhesive and an elastic bandage
(Coban™, 3 M Health care, U.S.A.). Mice were sacri-
ficed at 0.5, 1, 3, 6, 12, 24, 48 and 72 h (n = 8) after ap-
plication of the patch. The blood samples were taken
from the abdominal artery using a heparin-treated needle,
centrifuged at 1,500 g for 10 min, and stored at –70
until analysis.
To assess the analgesic potency of BupredermTM, a tail
flick test was performed [18]. Prescreened mice were
divided into 4 groups (0, 0.24, 0.8, 2.4 mg/patch, n = 12)
and were treated as described above. The pain threshold
was measured before (baseline) and after drug treatment
at 1, 3, 6, and 24 h after BupredermTM attachment. Mean
baseline latency was calculated from 3 repeated meas-
urements (20 min interval) before treatment. The tail
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flick analgesiometer (LE7106, Panlab, S.L., Spain) emits
radiant heat to the tail at a distance 1.5cm from the tip in
mice. The time from the onset of heat to the withdrawal
of the tail (tail-flick latency) was measured. The inten-
sity of the radiant heat was adjusted so that the baseline
latencies were between 2.5 and 3.5 seconds. To avoid
causing tissue damage, the heat stimulus automatically
switched off at 10 seconds (cut-off latency). Analgesic
potency was expressed as % maximum effect (ME).
2.4. Plasma Assay
The plasma concentrations of buprenorphine were
measured using a validated LC/MS/MS method. In brief,
plasma samples were spiked with naltrindole (internal
standard, I.S.) in deproteination solvent (MeOH) and
vortexed. After centrifugation, the supernatant was in-
jected onto the column. For analysis of buprenorphine, a
tandem quadrupole mass spectrometer (Quattro Ultima
Pt, Micromass, UK) coupled with an HPLC system
(1100 series, Agilent, U.S.A.) was utilized. The separa-
tion was performed on a Capcell pak C18 (2.0 mm × 150
mm, 5 µm, Shiseido, Japan) column using a mobile
phase consisting of 10 mM acetate buffer (pH 4.2) and
acetonitrile with a linear gradient (55/4530/70, v/v) for
15 min at a flow rate of 0.2 ml/min. The injection vol-
ume was 10 μL. Mass spectra were recorded with posi-
tive electrospray ionization (ESI+) and analysis was per-
formed using multiple reaction monitoring (MRM) with
a specific transition at 468.5555.05 for buprenorphine
and 414.555.3 for naltrindole.
The standard curve was linear over the concentration
range of 0.5-100 ng/ml for buprenorphine in plasma
sample with a typical correlation coefficient of r = 0.9946
or higher. The LOQ of buprenorphine was 0.5 ng/ml in
plasma. The mean intra- and inter-day assay coefficients
of variation were < 9% and the mean accuracy was 92-
109% over the concentration range studied (n = 5 at each
concentration).
2.5. Pharmacokinetic Analysis
Pharmacokinetic analysis was performed using non-
compartmental and compartmental methods. The area
under the curve (AUCt) of plasma concentration versus
time was calculated with the trapezoidal rule. We used a
modified two-compartment open model with lag time
and zero-order absorptions and first-order elimination
for the calculation of the pharmacokinetic parameters.
The model development was interactive with regard to
both the underlying data set and the selected model
structure. Models were constructed as series of differen-
tial equations using the ADAPT II software (D’Argenio
& Schumitzky, 1997). The fitting to individual data was
performed by weighted least-squares estimation, under
the assumption that the standard deviation of the meas-
urement error was a linear function of the measured
quantity. The goodness of fit and quality of the parame-
ter estimation were evaluated based on the parameter
correlation matrix, the sums of squares of residuals, vis-
ual examination of the distribution of residuals, and the
Akaike information criterion. As criteria for evaluating
the numeric identification of estimates, we used a coeffi-
cient of variation of < 0.5 and a correlation coefficient
threshold of 0.9.
Drug input (BTDScompartment 1) was assumed to
occur in compartment 2, 3 (zero order absorption)
whereas compartments 4 and 5 represented the central
compartment (distribution volume, V4) and the tissue
region for buprenorphine disposition, respectively.
First-order rate constants describing intercompartmental
transport are denoted by Kcp and Kpc.
2.6. Pharmacodynamic Analysis
To evaluate possible hysteresis between the pharmaco-
dynamic effect and buprenorphine plasma concentration,
the effect was plotted against the concentration, and the
data points were connected in time sequence. A slow
receptor-binding model was applied to link the plasma
concentrations of buprenorphine to the observed effects.
A slow receptor-binding model has been developed by
Shimada et al. on the basis of the in vitro binding data
for calcium-channel antagonists [19]. The following
hypothesis about ion-channel binding was included in
the pharmacokinetic-pharmacodynamic model to ac-
count for the possibility of a delay between plasma drug
concentration and effect. The model assumed that the
drug in plasma directly acted on the opioid receptor at
the target site with a second order association rate con-
stant (Kon, nM-1·h-1) and a first order dissociation rate
constant (Koff, h-1), (Figure 2); the differential equation
for the PK/PD analysis is as follows:
EKCEEK
dt
dE
offpon  )( max
(1)
where Cp is the drug concentration at a central compart-
ment, Kon is a second order association rate constant, and
Koff is a first order dissociation rate constant. The three
pharmacodynamic parameters (Kon, K
off, and Emax) were
estimated by the ADAPT II program with the use of the
previously estimated pharmacokinetic parameters. The
Kd was calculated according to the following equation:
on
off
dK
K
K
(2)
The adequacy of the models and of the estimated pa-
rameters was assessed from visual inspection of the
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curve fitting, the estimated variance of the residual error,
the plots of weighted residuals versus time, and the coef-
ficient of variation for all parameters.
3. RESULTS
3.1. Pharmacokinetic Analysis
The curve describing mean plasma concentrations of
buprenorphine versus time after transdermal application
is shown in Figure 3. The lines (solid, dotted, dashed)
represent the best fit of the pharmacokinetic model to the
measured concentration. A modified two-compartment
open model with lag time was chosen to describe the
data based on the weighted least-squares criterion and on
visual inspection of the fits. The estimated pharmacoki-
netic parameters are listed in Table 1. The Cmax and
AUCt values in the plasma showed linear increases with
dose.
3.2. Analgesic Effect
Figure 4 shows the results of the analgesic effect of
transdermal administration of buprenorphine·HCl to
mice determined by tail flick latency. Analgesic efficacy
of 3 patch dosages (0.24, 0.8, 2.4 mg/patch) were com-
pared over time (1, 3, 6, and 24 h after application) with
measurements at each time point.
BupredermTM induced prolongation of tail-flick la-
tency in a dose and time dependent manner. For the low
dose group (0.24 mg), the analgesic effect appeared after
3 h, maximum latency was attained at 6 h, and was
maintained for 24 h after patch application. For the me-
dium (0.8 mg) and high (2.4 mg) dose groups, the anal-
gesic effect appeared after 1 h, and maximum latency
was attained at 3 h and decreased slightly at 24 h after
patch application. No significant differences between
groups were observed at baseline.
The pharmacodynamic parameters for analgesic effect
after BTDS administration were estimated for each sub-
ject (Table 2). Fitting of the data using a slow receptor
binding model resulted in a set of mean pharmacody-
namic parameters. The prolongation of tail-flick latency
was clearly dose-dependent with the maximal predicted
latency (Emax) of 37.29 ± 15.22, 59.94 ± 21.39 and 91.39
± 38.51 % for 0.24, 0.8, 2.4 mg/patch, respectively.
3.3. Pharmacokinetic-Pharmacodynamic
Modeling of Analgesic Effect
Plotting the analgesic effect against the plasma concen-
tration of buprenorphine showed a counterclockwise
hysteresis loops (Figure 5) indicating a delay between
the change in plasma concentration and the onset of the
effects. There were significant differences between the
time reaching the peak plasma concentrations at 1 h
and the time attaining maximum analgesic effects at 3 h
after patch application.
The plasma concentrations of buprenorphine could be
linked to the observed effects by means of a slow recep-
tor-binding model, and the equilibrium between the
plasma drug concentration and the drug-receptor com-
plex could be characterized by the second-order rate
constant (kon) and the first order dissociation rate con-
stant (Koff). With the developed PK-PD model, the pa-
rameter of pharmacological interest such as Kd (dissocia-
tion rate constant) could be calculated from estimates of
Kon and Koff and the estimated in vivo Kd (0.69-0.82 nM)
values are similar to reported values (Kd = 0.76 ± 0.14
nM) [20]. Good agreement between the predicted and
observed values was noted for the rate of change in an-
algesic effect data (R2 = 0.822, 0.852 and 0.774 for 0.24,
K
c
p
K
p
c
Effect
D-R complex
K
off
K
o
n
Dose
2. Skin 4. Central 5. Peripheral
K
a
K
el
+
1 Patch
3. Depot
K
0
f
1-f K
a-slow
T
post-lag
Receptor
Figure 2. Slow receptor-binding models describing the analge-
sic effects of buprenorphine transdermal delivery system.
Time after patch application (hour)
0 12243648607
0
10
20
30
40
Concentration (ng/ml)
Concentration(ng/ml)
2
Time after patch application(hour)
Figure 3. Plasma buprenorphine concentration after a single
dose of 0.24mg, 0.8mg and 2.4mg patch to mice( mean value ±
S.D., n= 8). Data points are observed values [0.24 (), 0.8 ()
and 2.4 () mg/cm2], and the lines [0.24 (—), 0.8 (….) and 2.4
(– –) mg/cm2] are the result of weighted least-squares fitting
with the ADAPT II program.
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Time after patch application (hour)
0 12243648607
% Maximum Effect
2
0
20
40
60
80
100
Figure 4. Mean analgesic effect versus time after a single dose
of 0.24, 0.8 and 2.4mg buprenorphine patch to mice (mean
value ± S.D., n= 12). Data points are observed values [0.24 (),
0.8 () and 2.4 () mg/cm2], and the lines [0.24 (—), 0.8 (….)
and 2.4 (– –) mg/cm2] are the result of pharmacodynamic fit to
estimated analgesic efficacy from PK-PD model.
Table 1. Pharmacokinetic parameters for buprenorphine fol-
lowing a single dose of BupredermTM (0.24, 0.8, 2.4 mg/cm2).
Parameter Value
0.24 mg
Patch 0.8 mg Patch 2.4 mg Patch
Model independent parameters
aAUCt
(ng·h/ml)
104.25 ±
16.22 373.76 ± 63.45 815.54 ±
127.35
bCmax (ng/ml) 3.32 ± 0.61 9.34 ± 1.41 32.75 ± 7.82
cTmax (h) 1~24 1~24 1~24
dt1/2 (h) 49.33 ±
15.21 26.85 ± 16.34 33.37 ±
18.42
Model dependent parameters
eKel (1/h) 3.81 ± 0.58 2.56 ± 0.41 4.49 ± 0.75
fK0 (ng/cm2 h) 119.25 ±
16.53 420.22 ± 22.35 932.14 ±
43.56
gKa (1/h) 8.67 ± 1.25 3.61 ± 0.85 1.95 ± 0.92
hKa-slow (1/h) 0.20 ± 0.03 0.22 ± 0.05 0.51 ± 0.09
iTlag (h) 3.73 ± 0.62 0.38 ± 0.12 1.13 ± 0.43
jTpostlag(h) 5.09 ± 0.86 1.00 ± 0.32 6.40 ± 0.93
Pharmacokinetic parameter estimates from blood samples in the modi-
fied two-compartment open model following a single dose of Bu-
predermTM (0.24, 0.8, 2.4 mg/cm2). Data presented as mean values ±
S.D. (n = 8). aAUCt: Area under the curve of plasma concentration
versus time(t = 72 h); bCmax : Peak plasma concentration; cTmax: Corre-
sponding peak time; d t1/2: Elimination half life; eKel: Elimination rate
constant; fK0: Zero-order absorption rate constant; gKa: First order
absorption rate constant; hKa-slow: First order rate constant of slow ab-
sorption; iTlag, jTpostlag: Lag time.
Concentration (ng/ml)
0123
% Maximum Effect
0
20
40
60
80
100
%Maximum Effect
%Maximum Effect
(a)
Concentration (ng/ml)
0246
% Maximum Effect
8
0
20
40
60
80
100
(b)
Concentration (ng/ml)
0510 15 20 25 30
%ect Maximum Eff
0
20
40
60
80
100
Concentration (ng/ml)
Time after patch application(hour)
%Maximum Effect
Concentration (ng/ml)
%Maximum Effect
Concentration (ng/ml)
(c)
Figure 5. Mean plasma concentration of buprenorphine versus
the mean analgesic effects hysteresis plot following a single
administration of BupredermTM (A: 0.24 mg/patch, B: 0.8
mg/patch and C: 2.4 mg/patch) to mice. Data are the result of
pharmacokinetic-pharmacodynamic fit from PK-PD model.
The arrow indicates the time course direction.
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Table 2. Pharmacodynamic parameters estimated by means of
the weighted least-squares method with ADAPT II software.
Parameter 0.24 mg Patch 0.8 mg Patch 2.4 mg Patch
aEmax (%) 37.29 ± 15.22 59.94 ± 21.39 91.39 ± 38.51
bKon
(nM-1·h-1) 0.29 ± 0.12 7.81 ± 2.15 34.33 ± 8.36
cKoff (h-1) 0.10 ± 0.07 2.72 ± 0.85 14.15 ± 2.23
dKd (nM) 0.71 ± 0.13 0.69 ± 0.11 0.82 ± 0.18
The reported Kd value of buprenorphine to opioid receptor in rat brain
was 0.76 ± 0.14 nM (20). Data presented as mean values ± S.D. (n = 8).
aEmax: Maximum effect; bKon: Second order association rate constant;
cKoff : First order dissociation rate constant; dKd: Dissociation rate con-
stant;
0.8 and 2.4 mg/patch, respectively). Overall, the time
course of anti-nociceptive effect of a single dose of
BTDS was well represented by PK-PD modeling using a
slow receptor-binding model.
4. DISCUSSION
A new buprenorphine hydrogel matrix system, Bu-
predermTM was developed for a faster onset of therapeu-
tic effects using absorption enhancers incorporated in a
hydrogel base. The steady state flux of 2.7 μg/cm2·h was
achieved from BupredermTM (2.4 mg/cm2, 17.5 cm2, 42
mg/patch) to reach therapeutically effective target pla-
sma concentrations in humans (0.5-0.7 ng/ml), which
was demonstrated in ex vivo permeation study using
human skin [10].
In the present study, the PK-PD correlation of the an-
algesic effect of buprenorphine was determined in the
mice using a tail flick test following single application of
BupredermTM. Such thermal tail-flick test is most widely
and reliably used for revealing the potency of opioid
analgesics, especially useful for predicting analgesic
effects in humans [20,21], and therefore, can be consid-
ered a direct measure of buprenorphine effect. The as-
sessment of the PK-PD correlation of buprenorphine in
tail-flick assay is complicated by the availability of
sparse data for the anti-nociceptive effect since repeated
exposure to heat may have, by itself, altered the accu-
racy of pain threshold over repeated trials. The receptor
binding modeling helped to overcome the sampling re-
strictions for pharmacodynamics.
Following single patch application, the peak bupre-
norphine level in plasma was achieved at 1-24 h, and the
effective therapeutic drug concentration was maintained
for 72 h. The peak drug concentration was attained be-
tween 1 to 24h reaching plateau at constant steady-state
plasma concentration with zero-order absorption of bu-
prenorphine from BupredermTM. Afterwards, buprenor-
phine concentration was declined gradually until the
patch was removed at 72 h indicating that the buprenor-
phine absorption rate was not sustained for the duration
of patch application. The steady-state pharmacokinetic
profile that is typical of transdermal delivery system
depends on constant drug input. The rates of drug input
from TDS into systemic circulation are controlled by
penetration barriers(skin) and may be described in Fick’s
law term.
In reality, the drug permeation through skin may not
be constant and varies during patch application period
possibly due to changes in skin properies, decrease of
drug concentration in the matrix and depletion of en-
hancers in the process of drug delivery. The deviation
from the steady-state plasma levels of buprenorphine
after 24 h may partly be attributed to depletion of the
volatile penetration enhancer that is successfully applied
due to the unique features of hydrogel matrix system and
to changes in the drug concentration in the patch to a
certain extent since 5-10% of the loading dose seemed to
be absorbed based on the transdermal delivery rate de-
rived from experimental pharmacokinetics in mice.
The pharmacokinetics of buprenorphine in plasma
was well described by a modified two-compartment
open model with model-dependent pharmacokinetic pa-
rameters (Kcp, Kpc, K0, Ka, Kel). The goodness of fit and
quality of the parameter estimation were evaluated and
confirmed using coefficient of variations of < 0.5 and
correlation coefficient thresholds of 0.9 as criteria.
PK/PD correlation of buprenorphine was determined
in the mice measuring tail-flick latency as a pharmaco-
dynamic endpoint. Analgesic efficacy of 3 patch dosages
(0.24, 0.8, 2.4 mg/patch) were determined over time (1,
3, 6 and 24 h after application) with repeated measure-
ment at each time point. Application of buprenorphine
patch induced prolongation of tail-flick latency in a dose
and time-dependent manner. Maximum analgesic effect
was attained at 3-6 h and was maintained for 24 h after
patch application. The assessment of the PK-PD correla-
tion of buprenorphine in tail-flick assay is complicated
by the limited number of effect measurements that could
be taken from each individual mouse. The PD measure-
ments were made for total 4 time points in each animal
since repeated exposure to heat altered the accuracy of
pain threshold, as evidenced by an increase in pain
threshold at 24 h in the control group receiving the pla-
cebo patch (data not shown). Therefore, pharmacody-
namic parameters for analgesic effect after BTDS ad-
ministration were estimated by fitting the PD data using
a slow receptor binding model and time-dependent an-
algesic efficacy was estimated from PK-PD model. The
predicted analgesic effect data was in good agreement
with the observed values (R2 = 0.822, 0.852 and 0.774
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for 0.24, 0.8 and 2.4 mg/patch, respectively). From the
developed PK-PD model, Kd values (0.69-0.82 nM) that
were derived from the pharmacodynamic parameters
(Kon and Koff) are similar to the reported values (Kd =
0.76 ± 0.14 nM) [20] indicating that the established
PK-PD model well represents analgesic effect of BTDS.
Plotting the analgesic effect against the plasma con-
centration of buprenorphine resulted a counterclockwise
hysteresis loops indicating there was a delay between
plasma concentrations and the effects observed after
BTDS administration.
It is well known that the analgesic effect of buprenor-
phine is mediated by interaction with the μ-type of
opioid receptor [22,23] localized in various brain regions
and binding to the μ-receptor. is sustained due to its slow
receptor equilibration kinetics [14,24]. Hence, the time
course of buprenorphine effect is influenced by target
binding equilibration.
In conclusion, we were able to describe the analgesic
effect of buprenorphine transdermal delivery system
using a slow receptor-binding model. The established
PK-PD model successfully described the relationship
between plasma concentration and its analgesic efficacy
measured by the tail flick test. Our model might be use-
ful in estimation and prediction of onset, magnitude and
time course of concentration and pharmacological ef-
fects of BTDS and will be useful to simulate PK-PD
profiles with clinical regimens.
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