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Prediction of Sublingual Bioavailability of Buprenorphine in Newborns with Neonatal Abstinence
macokinetic Syndrome—
Model of Imatinib
Mesylate
and
its
Metabolite
in
Children
a
case
study
on
physiological
and
developmental
changes
using
NONMEM
and
SIMCYP
1
1
2
2
1
1
k , Bhuvana Jayaraman , Patrick Thompson , Susan Blaney , Peter Adamson and Jeffrey Barrett
1
Wu ,
2
Kraft ,
3
Ehrlich ,
1,4
Barrett
Di of Philadelphia,
Walter K Philadelphia,
Michelle
E Baylor College
JeffreyofSMedicine, Houston, TX.
cal Pharmacology and Therapeutics, The Children's Hospital
PA.
2
1Division
of Clinical Pharmacology & Therapeutics, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104; 2Department of Pharmacology and Experimental Therapeutics, Thomas
Jefferson University, Philadelphia, PA 19107; 3Department of Pediatric and Neurology, Thomas Jefferson University, Philadelphia, PA 19107; 4Department of Pediatrics, University of
Pennsylvania School of Medicine, Philadelphia, PA 19104
0.8
13000
20
8000
Observed 3000
Predicted Individual
IPRED
300
250
18
3
5.5
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7.0
PRED
96
0
8.5
9
0.4
0.2
2
19
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19
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28
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19 16
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16 181213
19 22
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169 13
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16 27
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12 2516 12
13 22 27
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27
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22
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13 6
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9 1522
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6 1919
22
DV
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0.0
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400 1000 600
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1000
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22
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27
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-1
19
28
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22
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16 27
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22
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25 25
12 12 22
1327
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Time (hours)
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1200
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2222
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27
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25
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•
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0
-1
19
19
22
919
1919
19
-2
-1 0.0
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Predicted Drug Concentration (ng/mL)
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•
500
-3
-3
Observed
Predicted Individual
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12
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IPRED
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27 22 2227 19
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16 16
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PRED
13
13
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0
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Residuals
PRED
1000
Residuals
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0
•
9
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18
100
200
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18 16
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22 16
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27
22
19 19
13
TIME
0.0
6
6
1613
161313
27
16
13 16
16 16
13
13
pharmacokinetics of BUP and NBUP based on data from a pilot clinical trial
in
-0.1 plasma
-0.1
Figure
2:
Top
panel:
Population
(PRED)
predicted,
individual
(IPRED)
12 newborn patients with NAS (Pediatrics, 2008, 122, e601-607).
concentrations
and
the
goodness
of
fit
plots
for
imatinib
Bottom
panel:
Population
(PRED)
• Population PK analysis was performed using non-linear mixed-effects modeling
-0.2
-0.2
CV)with the
%NONMEM
Intersubject
variability
(%CV)
software, Version VI, Level 1.1.
predicted,
individual
(IPRED)
plasma
concentrations
and
the
goodness
of
fit
plots
for
-0.3
-0.3
• One compartment model with first order absorption, metabolism, and
0.0
0.1
0.2
0.3
0
200
400
600
800
1000
0
200
400
600
800
1000
Time (hours)
Predicted Drug Concentration (ng/mL)
CGP74588
elimination was developed in describing the PK of BUP and NBUP.
6
16
13
13 13
13
0.1
27
6
6
22
22
0.0
6
Time (hr)
13
27
6
•
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46
100
80
60
40
0
20
Sublingual Bioavailability (%)
100
80
60
0
40
38
40
42
44
46
38
40
42
44
PMA (week)
PMA (week)
ID = 13
ID = 22
ID = 27
100
100
PMA (week)
100
38
ID = 18
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38
40
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40
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PMA (week)
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PMA (week)
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PMA (week)
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60
40
0
38
40
42
44
PMA (week)
iv
20
Sublingual Bioavailability (%)
80
60
40
0
20
Sublingual Bioavailability (%)
80
60
40
0
20
Sublingual Bioavailability (%)
80
60
40
0
20
80
80
Sublingual Bioavailability (%)
DISCUSSION AND CONCLUSIONS
The final model fits the observed imatinib data well
There appears to be no pharmacokinetic differences in the two
populations evaluated
CONCLUSIONS
Unlike in adults, the model
does not predict an increase in CL/F
• The higher BUP-to-NBUP ratio (0.7—19.19) than adults (0.165—1.4) has been observed in newborn patients studied.
between
single dose to steady state
It might be due to immature hepatic function in newborns and compliance to BUP sublingual administration.
• ID 6 showed the two highest BUP/NBUP ratio among 12 newborns examined. It might be due to large percentage of
There
appears
to be considerable
variablility
in F, possibly
due to
BUP dose
not being administrated
(medical record errors)
and/or analytical measurement
errors.
• Large individual variability has been observed in sublingual bioavailability . Higher values of bioavailability
enterohepatic
recirculation
observed might be due
to underestimated CL and/or overestimated CL .
• Sublingual bioavailability was estimated from 13.5% to 56.6% in the 9 neonates treated exclusively with BUP during
A number
ofmonth.
the The
subjects
inofthis
received
transfusions
on
a at
the first postnatal
bioavailability
these 9trial
neonates
except ID 28 was
increased gradually
by 13%
least during this period. Linear increase trend is observed when plotting sublingual bioavailability versus PMA for
each of the
9 neonates
studied. possibly contributes to the observed variability
routine
basis,
which
• Sublingual bioavailability of ID 13, 22, and 27 showed less linear increase with PMA, compared with that of all other
in patients.
V/F (Imatinib
8 to
30%
into
It might be due todistributes
enzyme induction ~
of CYP
3A, CYP
2C, and
UGTsRBCs)
caused by phenobarbital.
• Growth factors such as age, body weight can be important covariates to BUP exposure levels in newborns, given
the metabolite
fact of the significant
changes ofmay
body fathave
content and
enzyme levels
of CYP
3A, 2C8, 2C9,
and 2C19.
The
model
limited
value
given
the2C18
uncertainy
• Dose adjustment is needed for BUP therapy in newborns based on lower sublingual bioavailability estimated in
patients, parameters
compared to 50% of BUP sublingual bioavailability observed in adults, and drug-drug interaction
in newborn
structural
induced by phenobarbital. A larger, double-blind, properly powered clinical trial on BUP in young infants will
enhance and validate this model and simulation.
None of the covariates tested (weight, sex, age, albumin, study
population) were found
to have a significant effect on the observed
ACKNOWLEDGMENT
We cordially thank Dr. Masoud Jamei and Mr. Steve Marciniak in Simcyp Limited for their technical assistance to
variability
operation and installation of SIMCYP software in our BUP project.
sub
13
40
Sublingual Bioavailability (%)
100
80
60
40
400
600
800 1000 1200
40 42 44
46
Third Quartile AUC (mg.h/L)
PMA (week)
100
100
0
38
ID = 16
20
Sublingual Bioavailability (%)
50
0
0
700
20
150
100
Count
100
80
60
40
Sublingual Bioavailability (%)
80
6050
40
020
0
20
100 100
Count
150
200
13
9
27
25
22
18
-2
16
19
22
27
9
1500
6
19
9
0
•
200
15
19
13
1
100
TIME
18
3
15
-1
0.5
250
200
-8
1
0.4
Sublingual Bioavailability (%)
100
•
•
200 300 400 500 600
38 40
42 44 46
Median AUC (mg.h/L)
PMA (week)
ID = 15
60
CLN
dA
 Ka  A
dt
-4
dC
V2
 Ka  A  CLCR  C  CLCM  C
dt
dCm
V3
 CLCM  C  CLN  Cm
-6
dt
2
NBUP
Conc (ng/mL)
80
V3
(NBUP)
CLCR
-2
19
2000
60
0
CLCM
V2
(BUP)
200
300
400
38 40 42
44 46
First Quartile AUC (mg.h/L)
PMA (week)
100
0
100
T ime (hr)
1000
100
Count
43
40
39
41
PMA (week)
20
37
ID = 9
60
ka
-8
13000
2000
0
33 (28.4)
150
20
BUP/NBUP Ratio
5
10
15
43
PMA (week)
2500
SULTS
0
0
0
0
20
39
41
PMA (week)
2
16
0
BUP/NBUP Ratio
5
10
15
20
BUP/NBUP Ratio
5
10
15
20
BUP/NBUP Ratio
5
10
15
20
BUP/NBUP Ratio
5
10
15
37
Depot
ID = 6
Left: Population first quartile AUC
Middle: Median AUC
RESULTS Right: Population third quartile AUC
ID = 12
ID = 19
ID = 25
ID = 28
The observed values are indicated
by a blue vertical line, along with the
predictive check p-value (p-value is the
proportion of the simulated AUCs above the
observed value)
PMA: Postmenstrual Age
DV
ulation replicates of the observed data
PPK model. Distributions of the
to the observed values using
43
0
PRED
Conc (ng/mL)
• BUP is a semi-synthetic opioid derived from thebaine and used in clinics as an
analgesic and as a detoxification and maintenance treatment for opioid
2500
dependence.
• BUP is administered via intravenous and sublingual routes, since BUP has very
low oral bioavailability due to extensive first-pass metabolism.
2000
• BUP has large volume of distribution and is extensively metabolized to
norbuprenorphine (NBUP) by N-dealkylation mediated mainly by CYP3A4 (65%)
1500
and CYP2C8 (30%).
• BUP is metabolized in other metabolic pathways to a minor extent by CYP 2C9,
2C18, and 2C19 and to a major extent by CYP 3A.
1000
• Both BUP and NBUP undergo glucuronidation by UGT1A3, 1A8, and 2B7.
• NAS occurs in 55 to 94% of infants who are born to opioid-dependent mothers.
500the
• No data has been reported about the use of sublingual administration below
age of 4 year, especially for term infants with NAS. Therefore, there is a great
need to determine the PK characteristics to optimize pediatric therapy.
8000
39
41
PMA (week)
Sublingual
-4
Yes
(started at 121.09 hr
& stopped at 409.09 hr )
No
-6
15
BUP
3000
37
Weighted Residuals
0
220
40
2
ID = 19
20
AN28
43
0
39
39
41
PMA (week)
Sublingual Bioavailability (%)
2
37
40
AN27
4000
ID = 18
43
20
26
Weighted Residuals
2. To evaluate the developmental changes in newborns in order to assist dosing
optimization in ongoing clinical studies.
1
200
Co-medication
Time (hr)
with phenobarbital
No
No
No
Yes
(started at 143.29 hr 2
& stopped at 287.29 hr)
No
No
0
No
No
Yes
(started at 222.62 hr -2
& stopped at 381.5 hr)
No
15
16
11
24
47
AN25
39
41
PMA (week)
0
12000
180
37
BUP/NBP Ratio: Concentration Ratio of BUP/NBUP at the Same Time Point
PMA: Postmenstrual Age
8000
4000
MODEL DEVELOPMENT
s •ofNonlinear
the final
model
mixed-effect
modeling was employed to characterize the
160
43
Sublingual Bioavailability (%)
1
3
4
2
2
8000
INTRODUCTION
140
39
41
PMA (week)
WRES
DV
AN15
AN16
AN18
AN19
AN22
OBJECTIVES
goodness of fit plots,
precision of the
1. To characterize PK and sublingual bioavailability of buprenorphine (BUP) in
es in
the
intersubject
and
residual
target
population
during newborn
period.
25
• Simulation of intravenous clearance of BUP was conducted in the 12 newborn patients with NAS.
• In vitro
to simulate intravenous clearance in newborn patients.
p = 0.67 enzyme kinetic datap was
= 0.94 incorporated into SIMCYP
p = 0.98
* molecular weight, pKa, log P
* dose
* unbound fraction in plasma (fu)
* dose interval
* average renal clearance in adult
* blood to plasma ratio
* Vmax and Km values derived using human liver microsomes /recombinant CYPs
* unbound fraction in human liver microsomes /recombinant CYPs (fuMic)
Figure(CL
4: Predictive
Check
for
• Sublingual bioavailability was estimated by comparing intravenous clearance
)
obtained
from
SIMCYP
iv
Areaeffect
under
the curve
on
simulation to sublingual clearance (CLsub) generated using non-linear mixed
modeling
with(AUC)
NONMEM.
• Sublingual bioavailability—PMA profiles were drawn from the time theyday
were8born
till BUP
treatment completed for
(steady
state)
each of the 12 newborn patients.
0
50
Sublingual Bioavailability (%)
20
•
ID = 15
SIMULATION with SIMCYP
The population pharmacokinetic model is based on data from the 12 newborn patients with NAS. Three newborn
RESULTS
(continued)
patients (ID13, 22, & 27) were co-treated with phenobarbital during the certain period of treatment.
0
15
37
WRES
10
ID = 12
Figure 1: Observed concentration-time
profiles of imatinib
Left: Day1
Right: Day 8
0
Subject
Treatment
Treatment
Time (hr)
starting date
duration
from birth
(days)
(days)
AN06
1
14
AN09
4
15
AN12
4
17
16000
AN13
3
30
ID = 9
BUP/NBUP Ratio
5
10
15
Treatment information
43
WRES
scribe intersubject variability
ntersubject variability component to
, lnY=lnF+EPS(n)*EXP (ETA(n)
10 (83.3%)
2 (16.7%)
39
41
PMA (week)
ID = 16
WRES
5
Number
4000 (%)
Number (%)
DV
0
10 (83.3%)
2 (16.7%)
37
20
Gender
Male
Female
Race
White
Hispanic / Latino
Table 2
Number
(%)
8000
Number (%)
Observed concentration (g/L)
Postmenstrual Age
(PMA) (weeks)
Weight (kg)
Summary
39.28 (1.06)
39.31 (37, 41)
22 (11)
17 (11, 47)
41.9 (1.22)
42.15 (39.6, 43.55)
3.002 (0.347)
3.060 (2.39, 3.459)
0
Postnatal Age (days)
Statistic
Mean (SD)
Median (min, max)
Mean (SD)
Median (min, max)
16000
Mean (SD)
Median (min, max)
Mean12000
(SD)
Median (min, max)
BUP/NBUP Ratio
5
10
15
Covariate
Gestational Age (weeks)
0
at baseline
Observed concnentrations (g/L)
zero order, zero order, stepwise
ction were evaluated to describe the
ID = 6
Table 1 Summary of demographic characteristics for neonates (N = 12)
clinically as an analgesic and a detoxification agent and a maintenance
treatment for opioid dependence. No data, however, has been reported about
the use of sublingual administration of BUP below the age of 4 year, especially
for term infants with NAS.
Objectives: Characterize pharmacokinetics (PK) of BUP in newborn patients;
Evaluate the developmental changes in newborns in order to assist dosing 10000
optimization in ongoing clinical studies.
8000
Methods: In silico prediction of PK behavior and physiological development in
newborn patients were evaluated using SIMCYP. Intravenous clearance was 6000
predicted through physiologically based simulation method in SIMCYP. Based
4000
on sublingual clearance obtained from a one compartmental model developed
previously using NONMEM, individual changes of sublingual bioavailability 2000
were evaluated with physiological development in the first one and half month
0
during the newborn period.
Results: Intrinsic clearance of BUP in newborns were incorporated into enzyme
kinetic data obtained from literature. Change of sublingual bioavailability for
newborns was evaluated with bioavailability-postmenstrual age profiles.
Sublingual bioavailability of BUP was estimated as 8.9--56.6% in newborn
patients studied during the first one and half postnatal month.
Conclusion: Developmental considerations for the PK of BUP in newborns are
important for the characterization of the dose-exposure relationship. We16000
have
evaluated this from “bottom-up” and “top-down” approaches with SIMCYP and
NONMEM respectively and found these approaches to be complementary and
12000
valuable for clinical trial design and routine clinical care. Presumably they
would facilitate rational decision making in pediatric drug development as well.
ng NONMEM (version 5, level 1.1,
MODEL DESCRIPTION
RESULTS (continued)
0
ABSTRACT
Background: About 55% to 94% of infants born to opioid dependent mothers
THODS
(continued)
have neonatal abstinence syndrome (NAS). Buprenorphine (BUP) is used
46
38
40
42
44
PMA (week)
46