Great Ormond Street Hospital for Children NHS Trust London School of Pharmacy UCL Institute of Child Health Centre for Paediatric Pharmacy Research Developmental

Great Ormond Street Hospital

for Children NHS Trust

London School of Pharmacy

UCL Institute of Child Health

Centre for Paediatric Pharmacy Research Developmental

Pharmacokinetics of Diclofenac for Acute Pain

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





Centre for Paediatric Pharmacy Research

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)






Diclofenac

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






Diclofenac Pharmacodynamics

(McQuay 1998)







(McQuay 1998)Diclofenac dose (mg)

NNT for 50% pain relief







In children: (Romsing 1997)

pain scores

opioid requirements

paracetamol requirements






Paediatric Dosing

• 0.5mg/kg (Tay 2002)

• 1mg/kg (Mendham 1996)

• 2mg/kg (Nishina 2000)

• 2.5mg/kg (McGowan 1998)






Overview

• Introduction

• Aims/Methods

• Results

• Model Evaluation

• Dose Simulations

• Conclusions






Aim

Predict a paediatric dose which gives a similar AUC to

50mg in adults






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 VD

a priori• Simulations to predict dose






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 Data

Semi-Logarithmic Scatter Graph of Raw Diclofenac Concentrations Versus Time

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Paediatric Patients

Scatter Graph of Raw Diclofenac Concentrations Versus Time

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Paediatric Patients






Raw Data

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Time (hr)

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






Structural Model Building

• One compartment

• Two compartment

• Dual absorption one compartment

• Dual absorption two compartment






Final Structural Model

MTT1 Ka1 Dose 1 → T0 → … → Tn → DEPOT 1 CL N1 F1 CENTRAL N2 F2 Ke VD Dose 2 → T0 → … → Tn → DEPOT 2

Ka2 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. Figure XYZ: Schematic diagram of final model and overview of fixed-effects estimated in NONMEM.






Model Evaluation IPRED vs DV

Scatter Graph of Pooled Data: Dual Absorption Transit Model, Observed Concentrations Versus Individual

Predictions

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Individual predicted diclofenac concentration (nmol/L)

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Model Evaluation WRES vs Time

Scatter Graph of Pooled Data: Dual Absorption Compartment Transit Absorption Model, Weighted Residual Versus Time

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Model Evaluation

• Mainly focussed on simulated data from model

• Shrinkage






Model Evaluation Visual Predictive Check

Visual 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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Median

95th Percentile

5th Percentile

Raw Data






Model Evaluation Mirror Plots (Xpose 4)






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






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






Overview

• Introduction

• Aims/Methods

• Results

• Model Evaluation

• Dose Simulations

• Conclusions






Simulations

• Dose levels:– 0.5mg/kg– 1mg/kg– 1.5mg/kg– 2mg/kg

• AUC ratio:– Child AUC: Adult 50mg AUC






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






Conclusions

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

• Allometric size models adequately explained CL and VD changes






Acknowledgements

Jeff Rothwell, Rosemont Pharmaceuticals

Hussain Mulla & Brian Anderson

Anaesthetic and nursing staff at GOSH

Patients who took part






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 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.






Extra slides






Individual Plots (Adults)
























CovariatesScatter Graph of Standardised Clearance Estimates

from Final Model Versus Age

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ST

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/hr/

70kg

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Covariates

Scatter Graph of Standardised Volume of Distribution Estimates from Final Model Versus Age

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/F (L

/70k

g)






ShrinkageScatter Graph of Pooled Data: Dual Absorption Transit

Model, Observed Concentrations Versus Individual Predictions

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Scatter Graph of Peadiatric Data: Dual Absorption Compartment Transit Absorption Model, Observed

Concentration Versus Individual Predictions

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Pooled DV vs IPRED

Paediatric DV vs IPRED






Final Parameter EstimatesNONMEM estimates from final model.

Fixed effects (θ) Random effects (η) 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 93 CL/F (L/hr/70kg) 53.98 26 20 Residual variability (ε) (%): Adult data: 29 Paediatric data: 18






Dose Simulations

Documents

Great Ormond Street Hospital for Children NHS Trust London School of Pharmacy UCL Institute of Child Health Centre for Paediatric Pharmacy Research Developmental