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7/29/2019 Pharma Gel Slide

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London Schoolof Pharmacy

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DevelopmentalPharmacokinetics of

Diclofenac for Acute Pain

Standing JF, Howard RF, Johnston A,

Savage I, Wong ICK.


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UCL Institute of

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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


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Diclofenac

Drug No (%) of prescriptions(n=1053)

Diclofenac sodium 51 (5)

Morphine 48 (5)

Oxybutynin 23 (2)

Paracetamol 15 (1)

Ranitidine 12 (1)Sodium bicarbonate 6 (


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Diclofenac Pharmacodynamics

(McQuay 1998)


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(McQuay 1998)Diclofenac dose (mg)

NNT for 50%pain relief


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In children: (Romsing 1997)

pain scores opioid requirements paracetamol requirements


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UCL Institute of

Child Health

Centre for

Paediatric

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Research

Paediatric Dosing

0.5mg/kg (Tay 2002)

1mg/kg (Mendham 1996)

2mg/kg (Nishina 2000)

2.5mg/kg (McGowan 1998)


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Research

Overview

Introduction

Aims/Methods

Results Model Evaluation

Dose Simulations

Conclusions


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UCL Institute of

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Aim

Predict a paediatric dose

which gives a similar AUC to

50mg in adults


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UCL Institute of

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Research

Method

Adult rich data (30 volunteers)

Paediatric patients minor surgery

Pre-op 1mg/kg dose, 3 bloodsamples, digital watch

Pooled PopPK analysis withNONMEM (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 analysis:

100 subjects (30 adults 70 children)

558 serum concentrations

Weight range 9-93kg


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Raw Data

Semi-Logarithmic Scatter Graph of Raw Diclofenac

Concentrations Versus Time

1

10

100

1000

10000

0 2 4 6 8 10 12

Time (hr)

Diclofenacserum

concentration(nmol/L)

Adult volunteers

Paediatric Patients

Scatter Graph of Raw Diclofenac Concentrations Versus

Time

0

2000

4000

6000

8000

10000

0 2 4 6 8 10 12

Time (hr)

Diclofenacserum


Adult volunteers

Paediatric Patients


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Raw Data

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Diclofen

acserumconcentration(nmo

l/L)

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Time (hr)

Graphs Showing Raw Plots of Diclofenac Serum Concentration Versus Time for

Eight Adult Volunteers


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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 1

CL

N1 F1CENTRAL

N2 F2 Ke

VD

Dose 2 T0 Tn DEPOT 2Ka2

MTT2

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.


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Model Evaluation

IPRED vs DVScatter Graph of Pooled Data: Dual Absorption Transit

Model, Observed Concentrations Versus Individual

Predictions

0

1000

20003000

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7000

80009000

0 1000 2000 3000 4000 5000 6000 7000 8000 9000

Individual predicted diclofenac concentration (nmol/L)

Observeddiclofenac



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Model Evaluation

WRES vs Time

Scatter Graph of Pooled Data: Dual Absorption Compartment

Transit Absorption Model, Weighted Residual Versus Time

-15

-10

-5

0

5

10

15

0 12

Time (hr)

Weig

htedresidual


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Model Evaluation

Mainly focussed on simulated

data from model

Shrinkage


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Model Evaluation

Visual Predictive CheckVisual Predictive Check of Dual Absorption Transit Model: Median, 5th and 95th

percentile of simulated data and raw data of dual transit model

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2000

3000

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8000

9000

0 2 4 6 8 10 12

Time (hr)

Diclofenacs

erumconcentration(nm

ol/L)

Median

95th Percentile

5th Percentile

Raw Data


20/38

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UCL Institute of

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Model Evaluation

Mirror Plots (Xpose 4)


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Model Evaluation

Predictive Check Mean (standard deviation) AUC from

raw adult data calculated in

WinNonlin =

3368 (879)nmol.hr/L

Mean AUC from 3000 simulated

adults =2806 nmol.hr/L


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Age-Related Changes

Geometric mean standardised CL

values:

1-3 years: 52.9 L/hr/70kg

4-12 years: 50.8 L/hr/70kg

Adults: 50.4 L/hr/70kg

ADME adult equivalent by 1 year


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UCL Institute of

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Overview

Introduction

Aims/Methods

Results Model 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 years: 1.00

4-6 years: 1.08

7-12 years: 1.18


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Conclusions

1mg/kg optimum dose of

diclofenac for acute pain in

children

Allometric size models adequately

explained CL and VD changes


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Acknowledgements

Jeff Rothwell, Rosemont

Pharmaceuticals

Hussain Mulla & Brian Anderson

Anaesthetic and nursing staff at GOSH

Patients who took part


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ReferencesBlobaum AL & Marnett LJ. 2007. Molecular determinants for the selective inhibition of cyclooxygenase-2 by

lumiracoxib. The Journal of Biological Chemistry, 282:16379-90.

Davies NM & Anderson KE. 1997. Clinical pharmacokinetics of diclofenac. Clinical Pharmacokinetics,33:184-213.

Kleiber M. 1947. Body size and metabolic rate. Physiological Reviews, 27: 511-41.

Lau HSH, Chan K, Shum L, Adair S, Ross H, Eyring H, Gause D, John V. 1989. Dose proportionality ofdiclofenac sodium (Voltaren) in man. (conference abstract) Pharmaceutical Research, 6:S194.

McGowan PR, May H, Molnar Z, Cunliffe M. 1998. A comparison of three methods of analgesia in childrenhaving day case circumscision. Paediatric Anaesthesia, 8:403-7.

McQuay HJ & Moore RA. 1998. Postoperative analgesia and vomiting, with special reference to day-casesurgery: a systematic review. Health Technology Assessment 2:1-236, Winchester, UK.

Mendham JE, Mather SJ. 1996. Comparison of diclofenac and tenoxicam for postoperative analgesia with

and without fentanyl in children undergoing adenotonsillectomy or tonsillectomy. PaediatricAnaesthesia, 6:467-73.

Meibohm B, Lear S, Pancetta JC, Barrett JS. 2005. Population pharmacokinetic studies in pediatrics: issuesin design and analysis. The AAPS Journal, 7:E475-87.

Nishina K, Mikawa K, Shiga M, Takao Y, Maekawa N, Obara H. 2000, Diclofenac and flurbiprofen with orwithout clonidine for postoperative analgesia in children undergoing elective ophthalmological surgery.Paediatric Anaesthesia, 10:645-51.

Romsing J & Walther-Larsen S. 1997. Peri-operative use of nonsteroidal anti-inflammatory drugs in children:analgesic efficacy and bleeding. Anaesthesia, 52:673-83.

Rowlinson SW, Kiefer JR, Prusakiewicz JJ, Pawlitz JL, Kozak KR, Kalgutkar AS, Stallings WC, Kurumbail

RG, Marnett LJ. 2003. A novel mechanism of cyclooxygenase-2 inhibition involving interactions withSer-530 and Tyr-385. Journal of Biological Chemistry, 46:45763-9.

Savic R, Jonker DM, Kerbusch T, Karlsson MO. 2004. Evaluation of a transit compartment model versus alag time model for describing drug absorption delay. PAGE Abstract.

Tay CLM, Tan S. 2002. Diclofenac or paracetamol for analgesia in paediatric myringotomy outpatients.Anaesthesia ans Intensive Care, 30:55-9.

Turner S, Longworth A, Nunn AJ, Choonara I. 1998. Unlicensed and off label drug use in paediatric wards:prospective study. British Medical Journal, 316:343-5.


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Extra slides


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Individual Plots (Adults)


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Model Evaluation



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Model Evaluation



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Model Evaluation



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Covariates

Scatter Graph of Standardised Clearance Estimatesfrom Final Model Versus Age

0

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60

80

100

120

0 5 10 15 20 25 30

Age (years)

CLSTD

/F(L/hr/

70kg

)


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Covariates

Scatter Graph of Standardised Volume of Distribution

Estimates from Final Model Versus Age

0

5

10

15

20

25

0 5 10 15 20 25 30

Age (years)

VDSTD/F

(L/70kg)


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ShrinkageScatter Graph of Pooled Data: Dual Absorption Transit

Model, Observed Concentrations Versus Individual

Predictions

01000

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8000

9000

0 1000 2000 3000 4000 5000 6000 7000 8000 9000


Ob

serveddiclofenac

con

centration(nmol/L)

Scatter Graph o f Peadiatric Data: Dual Absorption

Compartment Transit Absorption Model, Observed

Concentration Ver sus Individual Predictions

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Observeddiclofenac


Pooled

DV vs

IPRED

PaediatricDV vs

IPRED


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Final Parameter EstimatesNONMEM 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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Dose Simulations

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