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DevelopmentalPharmacokinetics of
Diclofenac for Acute Pain
Standing JF, Howard RF, Johnston A,
Savage I, Wong ICK.
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NSAID
pKa ~ 4
Oral F(unchanged) = 60%
Protein binding > 99.7%(Davies 1997)
Linear PK between 50 and 150mg(Lau 1989)
Time dependent COX-2 inhibition(Blobaum 2007, Rowlinson 2003)
NH
Cl
Cl
O
OH
Diclofenac
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Diclofenac
Dru No (%) of prescriptions(n=1053)
Di lofena odiu 51 (5)
Morphine 48 (5)
xybutynin 23 (2)
ara eta ol 15 (1)
anitidine 12 (1)odiu bi arbonate 6 (
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Diclofenac Pharmacodynamics
(McQuay 1998)
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Diclofenac Pharmacodynamics
(McQuay 1998)Diclofenac dose (mg)
NNT for 50
pain relief
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Diclofenac Pharmacodynamics
In children: (Romsing 1997)
q pain scores
q opioid requirements
q paracetamol requirements
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Paediatric Dosing
0.5mg/kg (Ta 2002)
1mg/kg ( endham 1996)
2mg/kg (Nishina 2000)
2.5mg/kg( cGowan 1998)
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Overview
Introduction
Aims/ ethods
Results
odel Evaluation
Dose Simulations Conclusions
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Aim
Predict a paediatric dosewhich gives a similar AUC to
50mg in adults
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Method
Adult rich data (30 volunteers)
Paediatric patients minor surger
Pre-op 1mg/kg dose, 3 bloodsamples, digital watch
Pooled PopPK anal sis withNON E (FOCE INTER)
Allometric scaling on CL and VDa priori
Simulations to predict dose
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Demographics
74 children recruited:
3 spat out dose
1 refused to be anaesthetised
Pooled anal sis:
100 subjects (30 adults 70 children)
558 serum concentrations
Weight range 9-93kg
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Raw Data
Sem i-Lo arithmic Sca tter Graph of Ra w D iclofenac
Co nce ntrations Versus Time
1
10
100
1000
10000
0 2 4 6 8 10 12
Time hr
Diclofenacserum
concentrationnmol
Adult volunteers
Paediatric Patients
Sc atter Graph of Ra w D iclofenac C onc entrations VersusTime
0
2000
4000
6000
8000
10000
0 2 4 6 8 10 12
Time hr
Diclofenacserum
concentrationnmol
Adult volunteers
Paediatric Patients
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Raw Data
0
500
1000
1500
2000
2500
3000
3500
4000
4500
5000
0 2 4 6 8
DiclofenacserumconcentrationnmolL
0
500
1000
1500
2000
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3500
4000
4500
5000
0 1 2 3 4 5 6 7
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0 1 2 3 4 5 6 7
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0 1 2 3 4 5 6 7
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0 1 2 3 4 5 6 7
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0 1 2 3 4 5 6 7
0
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1500
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3500
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0 1 2 3 4 5 6 7
Time hr
Graphs Showing Raw Plots of Diclofenac Serum Concentration ersus Time forEight Adult olunteers
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Structural Model Building
One compartment
Two compartment Dual absorption one compartment
Dual absorption two compartment
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Final Structural Model
MTT1
Ka1
Dose 1 T0 Tn DEPOT 1CL
N1 F1CENTRAL
N2 F2 Ke
VD
Dose 2 T0 Tn DEPOT 2
Ka2MTT2
Tn = Transit compartment.
The following fixed effects were estimated in NONMEM:
MTT1 = Mean transit time into first depot compartment (hr).N1 = Number of transit compartments prior to first depot compartment.F1 = Fraction absorbed from first depot compartment.t1/2A1 = Absorption half-life from first depot compartment (hr) = ln2/Ka1.MTT2 = Mean transit time into second depot compartment (hr).N2 = Number of transit compartments prior to second depot compartment.F2 = Fraction absorbed from second depot compartment (fixed to = 1 F1).t1/2A2 = Absorption half-life from second depot compartment (hr) = ln2/Ka2.VD = Volume of distribution (L).CL = Clearance (L/hr) = VD x Ke.
Figure XYZ: Schematic diagram of final model and overview of fixed-effectsestimated in NONMEM.
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Model Evaluation
IPRED vs DScatter Graph of Pooled Data: Dual bsorption Transit
Model Observed Concentrations ersus Individual
Predictions
0
1000
2000
3000
4000
5000
6000
7000
8000
9000
0 1000 2000 3000 4000 5000 6000 7000 8000 9000
Individual predicted diclofenac concentration nmol L
Observeddiclofenac
concentra
tionnmolL
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Model Evaluation
WRES vs TimeScatter Graph of Pooled ata ual sorption Compartment
Transit sorption Model Wei hted Residual ersus Time
-15
-10
-5
0
5
10
15
0 12
Time hr
Weihtedresidual
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Model Evaluation
ainl focussed on simulated
data from model
Shrinkage
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Model Evaluation
isual Predictive Checkisual Predictive Check of ual sorption Trans it Model Median th and thpercentile of simulated data and ra data of dual transit model
0
1000
2000
3000
4000
5000
6000
7000
8000
9000
0 2 4 6 8 10 12
Time hr
iclofenacs
erumconcentrationnmo
Median
95th Percentile
5th Percentile
Raw Data
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Model Evaluation
Mirror Plots (Xpose 4)
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Model Evaluation
Predictive Check ean (standard deviation) AUC fromraw adult data calculated in
WinNonlin =
3368 (879)nmol.hr L
ean AUC from 3000 simulated
adults =2806 nmol.hr L
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Age Related Changes
Geometric mean standardised CL
values:
1-3 ears: 52.9 L/hr/70kg 4-12 ears: 50.8 L/hr/70kg
Adults: 50.4 L/hr/70kg
ADME adult equivalent y 1 year
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Overview
Introduction
Aims/ ethods
Results
odel Evaluation
Dose Simulations Conclusions
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Simulations
Dose levels:
0.5mg/kg
1mg/kg 1.5mg/kg
2mg/kg
AUC ratio:
Child AUC: Adult 50mg AUC
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Dose Simulations
Best dose = 1mg/kg:
Paediatric AUC: Adult AUC Ratio
1-3 ears: 1.00
4-6 ears: 1.08
7-12 ears: 1.18
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Conclusions
1mg/kg optimum dose of
diclofenac for acute pain in
children
Allometric size models adequatel
e plained CL and VD changes
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Acknowledgements
Jeff Rothwell, Rosemont
Pharmaceuticals
Hussain ulla & Brian AndersonAnaesthetic and nursing staff at GOSH
Patients who took part
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Extra slides
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Individual Plots (Adults)
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Model Evaluation
Mirror Plots (Xpose 4)
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Mirror Plots (Xpose 4)
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Mirror Plots (Xpose 4)
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Covariates
Scatter Graph of Standardised Clearance stimates
from inal odel ersus e
0
20
40
60
80
100
120
0 5 10 15 20 25 30
e years
CLS
T
Lhr
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Covariates
Scatter Graph of Standardised olume of istri ution
stimates from inal odel ersus e
0
5
10
15
20
25
0 5 10 15 20 25 30
e years
ST
L
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ShrinkageScatter Graph of Pooled ata ual sorption Transit
odel O ser ed Concentrations ersus Indi idual
Predictions
0
10002000
3000
4000
5000
6000
7000
8000
9000
0 100 0 2 000 3 000 4 00 0 5 000 6 000 7 00 0 8 00 0 90 00
Indi
idual predicted diclofenac concentration
nmol
L
O
ser
eddiclofenac
conce
ntration
nmol
L
Scatter Graph of Peadiatric
ata
ual
sorption
Compartment Transit
sorption
odel O
se r
ed
Concentration
ersus Indi
idual Predictions
0
100 0
2000
3000
4000
5000
6000
7000
8000
9000
0 10 00 2 00 0 3 00 0 4 00 0 5 00 0 6 00 0 7 00 0 8 00 0 9 00 0
Indi
idual predicted diclofenac concentr ationnmol
L
O
ser
!
eddiclofenac
concentration
"
nmol
# L$
Pooled
DV vs
IPRED
PaediatricDV vs
IPRED
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Final Parameter Estimates
NONMEM estimates from final model.
Fixed effects () Random effects ()
Parameter Estimate Inter-individual
variability (%)
Between occasion
variability (%)
MTT1 (hr) 0.68 82 -
N1 1.03 102 -F1 0.70 24 -
t1/2A1 (hr) 0.09 31 -
MTT2 (hr) 1.37 117 -
N2 41.60 147 -
t1/2A2 (hr) 1.06 49 -
VD/F (L/70kg) 4.84 54 93CL/F (L/hr/70kg) 53.98 26 20
Residual variability () (%):
Adult data: 29
Paediatric data: 18
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