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DOI 10.1007/s40262-012-0023-8
Abstract
Background Peripherally acting opioids, particularly
peripheral j-opioid agonists, may be effective for treating
visceral pain by activating receptors expressed on afferent
nerves within the gut.
Objective The objective of this study was to investigate
the pharmacokinetic/pharmacodynamic profile of a novel
peripherally selective j-opioid agonist, CR665 (JNJ38488502), and compare it to that of oxycodone, a nonselective brain-penetrant opioid.
Methods In a randomized, placebo-controlled, doubleblind, three-way crossover study, healthy male volunteers
were administered CR665 (0.36 mg/kg, intravenous),
oxycodone (15 mg, oral) or placebo (intravenous and oral),
followed by assessment of visceral pain tolerance thresholds (VPTT) measured as volume of water (mL) in the
bag placed on an oesophageal probe. Plasma drug concentration data were used to generate pharmacokinetic
models, which were then used to fit the VPTT data using
NONMEM VI to generate population pharmacokinetic/
pharmacodynamic models.
Results CR665 kinetics were optimally fitted with a
two-compartment model, while oxycodone kinetics were
best described by a one-compartment model with transit
compartment absorption feeding directly into the central
compartment. For both drugs, the plasma concentration
effects on VPTT were best fit by a direct linear model,
i.e. without the concentrationanalgesia delay characteristic of brain-penetrant opioids. The slope of oxycodone
(0.089 mL per ng/mL) was steeper than that of CR665
(0.0035 mL per ng/mL) for the plasma drug concentration
acting on the VPTT.
Conclusion The results are consistent with the peripheral
selectivity of CR665, as well as the possibility that
peripheral actions of oxycodone contribute to its visceral
analgesic efficacy.
S. Kell
ALZA Corporation, Mountain View, CA, USA
G. Y. Wong
Pfizer, Inc., Worldwide Research and Development,
South San Francisco, CA, USA
L. Arendt-Nielsen A. M. Drewes
Center for Sensory-Motor Interaction,
Department of Health Science and Technology,
Aalborg University, Aalborg, Denmark
1 Introduction
Visceral pain is prevalent in clinical practice and causes
challenges in pain management [1]. Currently, centrally
acting, non-selective opioid agonists are used in the treatment of visceral pain. However, inadequate analgesia and
undesirable adverse effects often limit their usage [2].
126
A. E. Olesen et al.
127
128
A. E. Olesen et al.
The combined data for the placebo and CR665 or oxycodone response for each subject were modelled together in
this stage of the analysis. The placebo response (if any) was
assumed to be additive with any drug response (that is, the
placebo data established what would have happened if the
drug dose was zero). Linear and maximum concentration
effect relationships were examined as described in Table 1.
For linear models, the concentrationeffect relationship was
described by the term slopeD (D for drug). Positive values
indicated concentration-dependent analgesia. The models
were characterized by the maximum effect (Emax) and the
concentration producing 50 % of the maximum effect
(EC50). Pain measures were related to either the measured
venous plasma concentration of drug (C) or concentration of
the drug in the hypothetical effect compartment (Ceff). The
Ceff was delayed relative to the plasma concentration by an
equilibrium rate constant between plasma and the effect
compartment (ke0). If the pain measures were not delayed
relative to the opioid plasma concentration (i.e. the elimination half-life for effectsite equilibrium [t,ke0] = 0), the
data would support a pharmacodynamic model without a
separate effect compartment. If the analgesic effects were
delayed relative to the opioid plasma concentration, e.g. due
to a requirement for transport across the bloodbrain barrier,
the data would support a pharmacodynamic model with an
effect compartment, with a delay quantified by a positive,
non-zero value of t,ke0.
2.6 Statistical Analysis
The parameter estimates obtained using NONMEM were
expressed as the population average value and the population parameter variability (its variability across the
population).
2.6.1 Model Evaluation
A predictive model check was used to validate the final
model using PsN version 3.4.2 [21, 22]. The final population pharmacokinetic and pharmacokinetic/pharmacodynamic model, including the final fixed and random effects,
were used to simulate a dataset 1,000 times for the subjects
studied. The 95 % confidence intervals for the simulated
plasma concentrationtime profile or effecttime profile
were plotted against the observed data [24, 25].
3 Results
Eighteen healthy, non-smoking, opioid-nave male volunteers (17 Caucasian and 1 Asian; ages 1943 years, median
25 years; bodyweight 62.494.5 kg, median 80.0 kg; BMI
20.527.4 kg/m2, median 23.6 kg/m2) completed the study.
Tested the assumption that drug concentrations did not influence the effect
Tested the assumption that the data could be described by a linear model with no effect
delay
Tested the assumption that the data could be described by a non-linear model with no
effect delay; high EC50 values made this model revert to a linear model
E = baseline ? slopeD 9 C
E = m 9 ln(C ? baseline)
E = baseline ? (Emax 9 C)/
(EC50 ? C)
Ceff0 = ke0 9 (C - Ceff)
7
As for model 4 but with a ke0 term
C plasma drug concentration, Ceff observed concentration in the effect compartment, Ceff0 estimated concentration in the effect compartment, E time course of the effect of the oxycodone dose, EC50 plasma drug
concentration at which there was a half-reduction in the pain score, Emax plasma drug concentration at which there was a maximum reduction in the pain score, IIV inter-individual variability, ke0 equilibrium rate
constant between plasma and the effect compartment, which was also a population parameter, m slope of the apparent linear segment of the log-transformed concentration versus response curve, PK pharmacokinetic,
slopeD concentrationeffect relationship
E = m 9 ln(Ceff ? baseline)
Tested the assumption that the data could be described by a linear model with no effect
delay
E = baseline ? slopeD 9 C
Purpose
Equation
Description
Model
100
10
CR665
N-oxide metabolite
1,000
1
0
0.5
1
1.5
Time (h)
2
100
10
0.1
0
0.5
Time (h)
1
1.5
2
3.1.1 CR665
130
A. E. Olesen et al.
CR665
Oxycodone
Placebo
a
Visceral pain tolerance threshold (mL)
30
IV infusion
k12
CR665
V1
k
V2
21
k13
25
b
20
Amount
A
N-oxide
V3
k30
MTT
ktr
Trans ktr
A1
ktr
Trans ktr
An 1
Trans ktr
An
Vd/F
CL/F
15
0.5
1.5
1.0
2.0
Time (h)
CR665
Placebo
60
Oxycodone
Placebo
60
50
40
30
20
10
50
40
30
20
10
0
0
0.5
1.0
1.5
Time (h)
2.0
0.5
1.0
1.5
2.0
Time (h)
V1 (L)
-1
Populationtypical value
[%RSE]
8.08 [8.33]
8.11 [6.939.60]
0.505 [0.3670.670]
k13 ( = k30) [h ]
0.501 [15.6]
k12 (h-1)
4.85 [9.65]
4.85 [3.795.70]
k21 (h-1)
0.0778 [13.1]
0.078 [0.0560.099]
V3 (L)
488 [21.1]
493 [315741]
0.0166 [65.1]
0.0155 [0.00120.0621]
xk12
0.0331 [57.4]
0.0314 [0.00410.0906]
xV3
0.164 [35.9]
0.145 [0.0540.274]
0.113 [12.9]
0.109 [0.0830.143]
Proportional
errorN-oxide
(%CV)b
0.0311 [17.2]
0.030 [0.0180.041]
Pharmacokinetic parameter values for CR665 following administration of 0.36 mg/kg as intravenous infusion. All parameters were
bodyweight normalized so the volumes were scaled with WT/median
bodyweight (80 kg), and rate constants with (WT/median bodyweight
[80 kg])-0.25
gastrointestinal absorption after oral administration provided the best fit to the data (the model is depicted in
Fig. 3). The parameters for this model are summarized in
Table 3. The absorption process was characterized by a
mean transit time of 0.295 h (17.7 min), with a typical
value of N (number of compartments in the transit
chain) = 4.88. Visual predicted check plots performed for
the oxycodone pharmacokinetic model are shown in Fig. 4.
The model seems to describe the data of oxycodone well as
the visual predicted check plots shows that the 2.5th, 50th
and 97.5th percentiles of the observed data are closely
followed by the simulated 2.5th, 50th and 97.5th percentiles. In addition, the areas of 95 % prediction intervals
around the 2.5th, 50th and 97.5th percentiles of the simulated data overlap the 2.5th, 50th and 97.5th percentiles of
the observed data.
131
3.2 Pharmacodynamics
3.2.1 Placebo
A baseline model was selected for the placebo measured
effect. As the study was a three-way crossover study,
the same placebo data were used for both the CR665 or
oxycodone pharmacodynamic modelling. In the final CR665
or oxycodone models similar estimates of the population
mean baseline of 21.7 and 21.0 mL as well as similar baseline IIV of 0.175 and 0.180 mL, respectively, were found
(see Table 4).
3.2.2 Cr665
Due to a large difference in concentrations of parent
compound and metabolite (Fig. 1), parent compound was
considered the driver for the dynamics and only parent
compound was included in the pharmacokinetic/pharmacodynamic modelling. The model with the best fit of the
data from the CR665 arm of the study was Model 1,
describing a linear relationship between the concentration
and the effect, with IIV in the baselineeffect relationship
and a proportional error model. There was a clear
advantage of Model 1 over the baseline model, Model 2
(OFV difference of [5, see Table 5), demonstrating a
significant analgesic effect of CR665 on the oesophageal
distension VPTT. This finding was supported by the
positive value of slopeD (concentrationeffect relationship) for this model (Table 4). Model 3 had a higher OFV
than Model 1. Models 4, 5 and 6 all had a significant
drop in the OFV but EC50 values for Model 4 were very
low (0.05 ng/mL), and the ke0 of Models 5 and 6 was low
and high, respectively. None of Models 4, 5 and 6 passed
the covariance step of NONMEM. The non-linear model
Emax Model 7 in Table 5 with an effect delay ke0 passed
the covariance step with an OFV difference of [10
compared to Model 1. The estimation of the parameters
were baseline 20.0 mL (95 % CI 14.525.5), ke0 3.61 h
(95 % CI 1.146.51), Emax 3.65 mL (95 % CI 2.075.23)
and EC50 11.2 ng/mL (95% CI 2.52 to 24.9). However,
considering the study design with a relatively sparse
number of pharmacodynamic samples and use of only
one dose level, the maximum effect of CR665 might not
have been obtained and, thus, Model 1 was selected as
the final pharmacokinetic/pharmacodynamic model for
CR665.
3.2.3 Oxycodone
The model with the best fit of the data from the oxycodone
arm of the study was Model 1, describing a linear relationship between the concentration and the effect, with IIV
132
A. E. Olesen et al.
1000
500
0.0
0.5
1.0
1.5
CR665 N-oxide
CR665
10
2.0
0.0
0.5
Time (h)
1.0
1.5
2.0
Oxycodone
60
50
40
30
20
10
0.0
0.5
Time (h)
1.0
1.5
2.0
Time (h)
dashed black lines, solid black lines and dashed black lines, respectively. The 95 % predicted confidence intervals around 2.5th, 50th and
97.5th percentiles of the simulated data are shown as coloured areas:
the 95 % confidence interval for the median (pink areas) and the 2.5th
and 97.5th percentiles (blue areas) of the simulated data
CL/F (L/h)
201 [5.12]
201 [185221]
V1/F (L)
356 [6.43]
355 [310401]
MTT (h)
0.295 [11.3]
0.300 [0.2400.380]
NN
-4.06 [9.29]
Nb
4.88 [2.618.31]
NC
xV1/F
xMTT
0.0527 [42.1]
0.192 [31.6]
0.0420 [0.0090.086]
0.190 [0.070.32]
xNNc
0.516 [52.3]
0.490 [0.0971.235]
0.0638 [41.4]
0.0700 [0.02000.1300]
0.131 [63.8]
0.098 [0.0220.295]
CL/F apparent clearance after oral administration, CV coefficient of variation, MTT mean transit time for absorption, N number of compartments
in the transit chain (untransformed), NC not calculated, NN number of compartments in the transit chain (logit transformed), RSE relative
standard error, V1/F apparent volume of the central compartment for the parent compound after oral administration of the drug
a
The logit transform constrained N to be between 1 and 200 via the equation N = 199 9 EXP(NN)/[1 ? EXP(NN)] ? 1
Additive
The residual errors (additive and proportional) represented the variability in the data that was unexplained by the model. The additive error was
the component of the total error that was the same regardless of the opioid concentration. The proportional error was the component of the total
error that was proportional to the concentration
Models 3 and 4 also converged and passed the covariance step with a non-significant drop in OFV and a significant drop in OFV [6, respectively. The estimation of
the parameters of direct Emax for Model 3 were baseline
21.1 mL (95 % CI 16.825.4), Emax 13.2 mL (95 % CI
10.016.4) and EC50 166 ng/mL (95 % CI 69.2 to 401).
However, considering the study design with a relatively
sparse number of pharmacodynamic samples and use of
0.175 [0.08150.268]
0.159 [0.07980.267]
0.18 [0.08750.273]
0.171 [0.0910.267]
21.0 [16.725.3]
21.3 [17.625.8]
Baseline IIV
(SE [95 % CI])
21.7 [17.525.9]
21.6 [17.826.5]
0.0793 [0.01340.145]
0.0797 [0.02320.152]
0.0035 [0.000870.0061]
0.0035 [0.000840.0060]
Concentrationeffect
relationship (slopeD)
(pain units per ng/mL
of compound [95 % CI])
NA
NA
17
17
17
Ceff0 = ke0 9 (C - Ceff), E = baseline ? slopeD 9 Ceff, IIV on baseline, ke0 and SlopeD
Ceff0 = ke0 9 (C - Ceff), E = baseline ? (Emax 9 Ceff)/(EC50 ? Ceff), IIV on baseline and ke0
14
13.626
14.194
6.394
8.151
7.45
5.302
C plasma drug concentration, C0 initial (fictive) or back-extrapolated plasma drug concentration at time zero following bolus intravenous injection, Ceff observed concentration in the effect
compartment, Ceff0 estimated concentration in the effect compartment, E time course of the effect of the oxycodone dose, EC50 plasma drug concentration at which there was a half-reduction in
the pain score, Emax plasma drug concentration at which there was a maximum reduction in the pain score, IIV inter-individual variability, ke0 equilibrium rate constant between plasma and the
effect compartment, which was also a population parameter, m slope of the apparent linear segment of the log-transformed concentration versus response curve, NOP number of estimated
parameters in the model including pharmacokinetics parameters, OFV objective function value, slopeD concentrationeffect relationship
Residual error models used for the pharmacodynamic part were proportion error models unless specified otherwise
16
14
13
NOP
Equation
Model
Table 5 Model-building steps for the CR665 pharmacokinetic/pharmacodynamic model and changes in the objective function value
DOFV
0.0407 [0.02760.0538]c
0.0400 [0.02900.0539]
BIC Bayesian information criterion, IIV inter-individual variability, NA not applicable, SE standard error, slopeD concentrationeffect relationship, VPTT visceral pain tolerance threshold
a
Measured as the volume of water in the bag placed on an oesophageal probe
b
The 95 % CIs of the parameter estimates were based on the asymptotic standard error for the parameter returned by NONMEM
c
Proportional error
d
Median parameter estimates of 1,000 bootstrap replicates [2.597.5 % range]
e
Additive error (the parameter was not significant if the confidence interval included zero); however, this additive error stabilized the model to converge
CR665
VPTT (mL)a
Population estimateb
Bootstrap estimated
Oxycodone
VPTT (mL)a
Population estimateb
Bootstrap estimated
134
A. E. Olesen et al.
Table 6 Model-building steps for the oxycodone and changes in the objective function value
Model
Equation
NOP
DOFV
15
13
21.972
15
0.459
16
6.498
Ceff0 = ke0 9 (C - Ceff), E = baseline ? slopeD 9 Ceff, IIV on baseline and SlopeD
16
4.828
15
5.279
Ceff0 = ke0 9 (C - Ceff), E = baseline ? (Emax 9 Ceff)/(EC50 ? Ceff), IIV on baseline, ke0, Emax and EC50
19
6.498
Residual error models used for the pharmacodynamic part were mixed error models
C plasma drug concentration, Ceff observed concentration in the effect compartment, Ceff0 estimated concentration in the effect compartment,
E time course of the effect of the oxycodone dose, EC50 plasma drug concentration at which there was a half-reduction in the pain score, Emax
plasma drug concentration at which there was a maximum reduction in the pain score, IIV inter-individual variability, ke0 equilibrium rate
constant between plasma and the effect compartment, which was also a population parameter, m slope of the apparent linear segment of the
log-transformed concentration versus response curve, NOP number of estimated parameters in the model including pharmacokinetics parameters,
OFV objective function value, slopeD concentrationeffect relationship
4 Discussion
4.2 Pharmacokinetics
Placebo
135
80
60
40
20
0.0
0.5
1.0
1.5
CR665
80
60
40
20
2.0
0.0
0.5
Time (h)
Placebo
80
60
40
20
0.0
0.5
1.0
1.0
1.5
2.0
1.5
2.0
Time (h)
1.5
2.0
Time (h)
Oxycodone
80
60
40
20
0.0
0.5
1.0
Time (h)
data are plotted as dashed black lines, solid black lines and dashed
black lines, respectively. The 95 % predicted confidence intervals
around 2.5th, 50th and 97.5th percentiles of the simulated data are
shown as coloured areas: the 95 % confidence interval for the median
(pink areas) and the 2.5th and 97.5th percentiles (blue areas) of the
simulated data
136
A. E. Olesen et al.
5 Conclusion
4.4 Peripheral Versus Central Effect?
Clinically used opioids are generally believed to exert their
main analgesic effects via l-opioid receptors in the CNS.
Consistent with this view, there is evidence for a delay in
the time course of the pharmacodynamic effect (i.e. relief
of somatic pain) with respect to the time course of the
plasma drug concentration following opioid administration
[9, 30]. This delay in the analgesic response relative to
the pharmacokinetic profile, described as hysteresis, is
usually considered a consequence of rate-limiting transport
across the bloodbrain barrier, in addition to other factors.
In principle, both the efficacy and the immediacy of visceral pain relief reported here could be explained by the
involvement of peripheral j-opioid receptors on visceral
afferents as rat studies have demonstrated that j-opioids
are more efficient than l-opioids in reducing visceral pain
[31]. However, from the present study, it is not possible to
make a clear evaluation of the effectdelay component and
therefore other explanations for the current observations
cannot at present be excluded, e.g. a very rapid uptake of
oxycodone into a CNS effect compartment.
137
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