7900-PAGE Presentation JFS 11.6.7

8/7/2019 7900-PAGE Presentation JFS 11.6.7

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Great OrmondStreet Hospital

for ChildrenNHS Trust

London School

of Pharmacy

UCL Institute ofChild Health

Centre for

PaediatricPharmacy

Research

DevelopmentalPharmacokinetics of

Diclofenac for Acute Pain

Standing JF, Howard RF, Johnston A,

Savage I, Wong ICK.


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London School

of Pharmacy


Centre for

PaediatricPharmacy

ResearchDiclofenac

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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London School

of Pharmacy


Centre for

PaediatricPharmacy

Research

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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London School

of Pharmacy


Centre for

PaediatricPharmacy

Research

Diclofenac Pharmacodynamics

(McQuay 1998)


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London School

of Pharmacy


Centre for

PaediatricPharmacy

Research


(McQuay 1998)Diclofenac dose (mg)

NNT for 50

pain relief


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London School

of Pharmacy


Centre for

PaediatricPharmacy

Research


In children: (Romsing 1997)

q pain scores

q opioid requirements

q paracetamol requirements


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London School

of Pharmacy


Centre for

PaediatricPharmacy

Research

Paediatric Dosing

0.5mg/kg (Ta 2002)

1mg/kg ( endham 1996)

2mg/kg (Nishina 2000)

2.5mg/kg( cGowan 1998)


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London School

of Pharmacy


Centre for

PaediatricPharmacy

Research

Overview

Introduction

Aims/ ethods

Results

odel Evaluation

Dose Simulations Conclusions


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London School

of Pharmacy


Centre for

PaediatricPharmacy

Research

Aim

Predict a paediatric dosewhich gives a similar AUC to

50mg in adults


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London School

of Pharmacy


Centre for

PaediatricPharmacy

Research

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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London School

of Pharmacy


Centre for

PaediatricPharmacy

Research

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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London School

of Pharmacy


Centre for

PaediatricPharmacy

Research

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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London School

of Pharmacy


Centre for

PaediatricPharmacy

Research

Raw Data

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

0 2 4 6 8

DiclofenacserumconcentrationnmolL

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Time hr

Graphs Showing Raw Plots of Diclofenac Serum Concentration ersus Time forEight Adult olunteers


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London School

of Pharmacy


Centre for

PaediatricPharmacy

Research

Structural Model Building

One compartment

Two compartment Dual absorption one compartment

Dual absorption two compartment


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London School

of Pharmacy


Centre for

PaediatricPharmacy

Research

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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London School

of Pharmacy


Centre for

PaediatricPharmacy

Research

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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London School

of Pharmacy


Centre for

PaediatricPharmacy

Research

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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London School

of Pharmacy


Centre for

PaediatricPharmacy

Research

Model Evaluation

ainl focussed on simulated

data from model

Shrinkage


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London School

of Pharmacy


Centre for

PaediatricPharmacy

Research

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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London School

of Pharmacy


Centre for

PaediatricPharmacy

Research

Model Evaluation

Mirror Plots (Xpose 4)


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London School

of Pharmacy


Centre for

PaediatricPharmacy

Research

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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London School

of Pharmacy


Centre for

PaediatricPharmacy

Research

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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London School

of Pharmacy


Centre for

PaediatricPharmacy

Research

Overview

Introduction

Aims/ ethods

Results

odel Evaluation

Dose Simulations Conclusions


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London School

of Pharmacy


Centre for

PaediatricPharmacy

Research

Simulations

Dose levels:

0.5mg/kg

1mg/kg 1.5mg/kg

2mg/kg

AUC ratio:

Child AUC: Adult 50mg AUC


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London School

of Pharmacy


Centre for

PaediatricPharmacy

Research

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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London School

of Pharmacy


Centre for

PaediatricPharmacy

Research

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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London School

of Pharmacy


Centre for

PaediatricPharmacy

Research

Acknowledgements

Jeff Rothwell, Rosemont

Pharmaceuticals

Hussain ulla & Brian AndersonAnaesthetic and nursing staff at GOSH

Patients who took part


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London School

of Pharmacy


Centre for

PaediatricPharmacy

Research

Extra slides


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London School

of Pharmacy


Centre for

PaediatricPharmacy

Research

Individual Plots (Adults)


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London School

of Pharmacy


Centre for

PaediatricPharmacy

Research

Model Evaluation



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London School

of Pharmacy


Centre for

PaediatricPharmacy

Research

Model Evaluation



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London School

of Pharmacy


Centre for

PaediatricPharmacy

Research

Model Evaluation



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London School

of Pharmacy


Centre for

PaediatricPharmacy

Research

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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London School

of Pharmacy


Centre for

PaediatricPharmacy

Research

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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London School

of Pharmacy


Centre for

PaediatricPharmacy

Research

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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London School

of Pharmacy


Centre for

PaediatricPharmacy

Research

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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London Schoolof Pharmacy


Centre for

PaediatricPharmacy

Research

Dose Simulations

Documents

7900-PAGE Presentation JFS 11.6.7