Developmental pharmacokinetics of diclofenac for acute pain
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Developmental Pharmacokinetics of Diclofenac for Acute Pain. Standing JF , Howard RF, Johnston A, Savage I, Wong ICK. Diclofenac. NSAID pKa ~ 4 Oral F (unchanged) = 60% Protein binding > 99.7% (Davies 1997) Linear PK between 50 and 150mg (Lau 1989)

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Developmental pharmacokinetics of diclofenac for acute pain l.jpg
Developmental Pharmacokinetics of Diclofenac for Acute Pain

Standing JF, Howard RF, Johnston A, Savage I, Wong ICK.


Diclofenac l.jpg
Diclofenac

  • 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)


Diclofenac3 l.jpg
Diclofenac

  • Most common “off-label”(Turner 1998)



Diclofenac pharmacodynamics5 l.jpg
Diclofenac Pharmacodynamics

NNT for 50% pain relief

Diclofenac dose (mg)

(McQuay 1998)


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Diclofenac Pharmacodynamics

In children: (Romsing 1997)

 pain scores

 opioid requirements

 paracetamol requirements


Paediatric dosing l.jpg
Paediatric Dosing

  • 0.5mg/kg (Tay 2002)

  • 1mg/kg (Mendham 1996)

  • 2mg/kg (Nishina 2000)

  • 2.5mg/kg (McGowan 1998)


Overview l.jpg
Overview

  • Introduction

  • Aims/Methods

  • Results

  • Model Evaluation

  • Dose Simulations

  • Conclusions


Slide9 l.jpg
Aim

Predict a paediatric dose which gives a similar AUC to 50mg in adults


Method l.jpg
Method

  • Adult rich data (30 volunteers)

  • Paediatric patients – minor surgery

  • Pre-op 1mg/kg dose, 3 blood samples, digital watch

  • Pooled PopPK analysis with NONMEM (FOCE INTER)

  • Allometric scaling on CL and VDa priori

  • Simulations to predict dose


Demographics l.jpg
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



Raw data13 l.jpg

Graphs Showing Raw Plots of Diclofenac Serum Concentration Versus Time for Eight Adult Volunteers

Time (hr)

Raw Data


Structural model building l.jpg
Structural Model Building Versus Time for Eight Adult Volunteers

  • One compartment

  • Two compartment

  • Dual absorption one compartment

  • Dual absorption two compartment


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Final Structural Model Versus Time for Eight Adult Volunteers


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Model Evaluation IPRED vs DV Versus Time for Eight Adult Volunteers


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Model Evaluation WRES vs Time Versus Time for Eight Adult Volunteers


Model evaluation l.jpg
Model Evaluation Versus Time for Eight Adult Volunteers

  • Mainly focussed on simulated data from model

  • Shrinkage


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Model Evaluation Visual Predictive Check Versus Time for Eight Adult Volunteers


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Model Evaluation Mirror Plots (Xpose 4) Versus Time for Eight Adult Volunteers


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Model Evaluation Predictive Check Versus Time for Eight Adult Volunteers

  • 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


Age related changes l.jpg
Age-Related Changes Versus Time for Eight Adult Volunteers

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


Overview23 l.jpg
Overview Versus Time for Eight Adult Volunteers

  • Introduction

  • Aims/Methods

  • Results

  • Model Evaluation

  • Dose Simulations

  • Conclusions


Simulations l.jpg
Simulations Versus Time for Eight Adult Volunteers

  • Dose levels:

    • 0.5mg/kg

    • 1mg/kg

    • 1.5mg/kg

    • 2mg/kg

  • AUC ratio:

    • Child AUC: Adult 50mg AUC


Dose simulations l.jpg
Dose Simulations Versus Time for Eight Adult Volunteers

Best dose = 1mg/kg:

Paediatric AUC: Adult AUC Ratio

1-3 years: 1.00

4-6 years: 1.08

7-12 years: 1.18


Conclusions l.jpg
Conclusions Versus Time for Eight Adult Volunteers

  • 1mg/kg optimum dose of diclofenac for acute pain in children

  • Allometric size models adequately explained CL and VD changes


Acknowledgements l.jpg
Acknowledgements Versus Time for Eight Adult Volunteers

Jeff Rothwell, Rosemont Pharmaceuticals

Hussain Mulla & Brian Anderson

Anaesthetic and nursing staff at GOSH

Patients who took part


References l.jpg
References Versus Time for Eight Adult Volunteers

Blobaum 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 of diclofenac 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 children having day case circumscision. Paediatric Anaesthesia, 8:403-7.

McQuay HJ & Moore RA. 1998. Postoperative analgesia and vomiting, with special reference to day-case surgery: 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. Paediatric Anaesthesia, 6:467-73.

Meibohm B, Lear S, Pancetta JC, Barrett JS. 2005. Population pharmacokinetic studies in pediatrics: issues in 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 or without 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 with Ser-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 a lag 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 Versus Time for Eight Adult Volunteers


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Individual Plots (Adults) Versus Time for Eight Adult Volunteers


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Model Evaluation Mirror Plots (Xpose 4) Versus Time for Eight Adult Volunteers


Model evaluation mirror plots xpose 432 l.jpg
Model Evaluation Mirror Plots (Xpose 4) Versus Time for Eight Adult Volunteers


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Model Evaluation Mirror Plots (Xpose 4) Versus Time for Eight Adult Volunteers


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Covariates Versus Time for Eight Adult Volunteers


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Covariates Versus Time for Eight Adult Volunteers


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Shrinkage Versus Time for Eight Adult Volunteers

Pooled DV vs IPRED

Paediatric DV vs IPRED


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Final Parameter Estimates Versus Time for Eight Adult Volunteers


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Dose Simulations Versus Time for Eight Adult Volunteers


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