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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.
Great Ormond Street Hospital
for Children NHS Trust
London School of Pharmacy
UCL Institute of Child Health
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)
Great Ormond Street Hospital
for Children NHS Trust
London School of Pharmacy
UCL Institute of Child Health
Centre for Paediatric Pharmacy Research
Diclofenac
• Most common “off-label” (Turner 1998)
Great Ormond Street Hospital
for Children NHS Trust
London School of Pharmacy
UCL Institute of Child Health
Centre for Paediatric Pharmacy Research
Diclofenac Pharmacodynamics
(McQuay 1998)
Great Ormond Street Hospital
for Children NHS Trust
London School of Pharmacy
UCL Institute of Child Health
Centre for Paediatric Pharmacy Research
Diclofenac Pharmacodynamics
(McQuay 1998)Diclofenac dose (mg)
NNT for 50% pain relief
Great Ormond Street Hospital
for Children NHS Trust
London School of Pharmacy
UCL Institute of Child Health
Centre for Paediatric Pharmacy Research
Diclofenac Pharmacodynamics
In children: (Romsing 1997)
pain scores
opioid requirements
paracetamol requirements
Great Ormond Street Hospital
for Children NHS Trust
London School of Pharmacy
UCL Institute of Child Health
Centre for Paediatric Pharmacy Research
Paediatric Dosing
• 0.5mg/kg (Tay 2002)
• 1mg/kg (Mendham 1996)
• 2mg/kg (Nishina 2000)
• 2.5mg/kg (McGowan 1998)
Great Ormond Street Hospital
for Children NHS Trust
London School of Pharmacy
UCL Institute of Child Health
Centre for Paediatric Pharmacy Research
Overview
• Introduction
• Aims/Methods
• Results
• Model Evaluation
• Dose Simulations
• Conclusions
Great Ormond Street Hospital
for Children NHS Trust
London School of Pharmacy
UCL Institute of Child Health
Centre for Paediatric Pharmacy Research
Aim
Predict a paediatric dose which gives a similar AUC to
50mg in adults
Great Ormond Street Hospital
for Children NHS Trust
London School of Pharmacy
UCL Institute of Child Health
Centre for Paediatric Pharmacy Research
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
Great Ormond Street Hospital
for Children NHS Trust
London School of Pharmacy
UCL Institute of Child Health
Centre for Paediatric Pharmacy Research
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
Great Ormond Street Hospital
for Children NHS Trust
London School of Pharmacy
UCL Institute of Child Health
Centre for Paediatric Pharmacy Research
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)
Dic
lofe
nac s
eru
m
co
ncen
trati
on
(n
mo
l/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)
Dic
lofe
nac s
eru
m
co
ncen
trati
on
(n
mo
l/L
)Adult volunteers
Paediatric Patients
Great Ormond Street Hospital
for Children NHS Trust
London School of Pharmacy
UCL Institute of Child Health
Centre for Paediatric Pharmacy Research
Raw Data
0
500
1000
1500
2000
2500
3000
3500
4000
4500
5000
0 2 4 6 8
Dic
lofe
nac s
eru
m c
on
cen
trati
on
(n
mo
l/L
)
0
500
1000
1500
2000
2500
3000
3500
4000
4500
5000
0 1 2 3 4 5 6 7
0
500
1000
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2500
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3500
4000
4500
5000
0 1 2 3 4 5 6 7
0
500
1000
1500
2000
2500
3000
3500
4000
4500
5000
0 1 2 3 4 5 6 70
500
1000
1500
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2500
3000
3500
4000
4500
5000
0 1 2 3 4 5 6 7
0
500
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3500
4000
4500
5000
0 1 2 3 4 5 6 7
0
500
1000
1500
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3500
4000
4500
5000
0 1 2 3 4 5 6 7
0
500
1000
1500
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2500
3000
3500
4000
4500
5000
0 1 2 3 4 5 6 7
0
500
1000
1500
2000
2500
3000
3500
4000
4500
5000
0 1 2 3 4 5 6 7
Time (hr)
Graphs Showing Raw Plots of Diclofenac Serum Concentration Versus Time for Eight Adult Volunteers
Great Ormond Street Hospital
for Children NHS Trust
London School of Pharmacy
UCL Institute of Child Health
Centre for Paediatric Pharmacy Research
Structural Model Building
• One compartment
• Two compartment
• Dual absorption one compartment
• Dual absorption two compartment
Great Ormond Street Hospital
for Children NHS Trust
London School of Pharmacy
UCL Institute of Child Health
Centre for Paediatric Pharmacy Research
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.
Great Ormond Street Hospital
for Children NHS Trust
London School of Pharmacy
UCL Institute of Child Health
Centre for Paediatric Pharmacy Research
Model Evaluation IPRED vs DV
Scatter Graph of Pooled Data: Dual Absorption Transit Model, Observed Concentrations Versus Individual
Predictions
0100020003000400050006000700080009000
0 1000 2000 3000 4000 5000 6000 7000 8000 9000
Individual predicted diclofenac concentration (nmol/L)
Ob
serv
ed d
iclo
fen
ac
con
cen
trat
ion
(n
mo
l/L)
Great Ormond Street Hospital
for Children NHS Trust
London School of Pharmacy
UCL Institute of Child Health
Centre for Paediatric Pharmacy Research
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)
Wei
gh
ted
res
idu
al
Great Ormond Street Hospital
for Children NHS Trust
London School of Pharmacy
UCL Institute of Child Health
Centre for Paediatric Pharmacy Research
Model Evaluation
• Mainly focussed on simulated data from model
• Shrinkage
Great Ormond Street Hospital
for Children NHS Trust
London School of Pharmacy
UCL Institute of Child Health
Centre for Paediatric Pharmacy Research
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
0
1000
2000
3000
4000
5000
6000
7000
8000
9000
0 2 4 6 8 10 12
Time (hr)
Dic
lofe
na
c s
eru
m c
on
ce
ntr
ati
on
(n
mo
l/L)
Median
95th Percentile
5th Percentile
Raw Data
Great Ormond Street Hospital
for Children NHS Trust
London School of Pharmacy
UCL Institute of Child Health
Centre for Paediatric Pharmacy Research
Model Evaluation Mirror Plots (Xpose 4)
Great Ormond Street Hospital
for Children NHS Trust
London School of Pharmacy
UCL Institute of Child Health
Centre for Paediatric Pharmacy Research
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
Great Ormond Street Hospital
for Children NHS Trust
London School of Pharmacy
UCL Institute of Child Health
Centre for Paediatric Pharmacy Research
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
Great Ormond Street Hospital
for Children NHS Trust
London School of Pharmacy
UCL Institute of Child Health
Centre for Paediatric Pharmacy Research
Overview
• Introduction
• Aims/Methods
• Results
• Model Evaluation
• Dose Simulations
• Conclusions
Great Ormond Street Hospital
for Children NHS Trust
London School of Pharmacy
UCL Institute of Child Health
Centre for Paediatric Pharmacy Research
Simulations
• Dose levels:– 0.5mg/kg– 1mg/kg– 1.5mg/kg– 2mg/kg
• AUC ratio:– Child AUC: Adult 50mg AUC
Great Ormond Street Hospital
for Children NHS Trust
London School of Pharmacy
UCL Institute of Child Health
Centre for Paediatric Pharmacy Research
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
Great Ormond Street Hospital
for Children NHS Trust
London School of Pharmacy
UCL Institute of Child Health
Centre for Paediatric Pharmacy Research
Conclusions
• 1mg/kg optimum dose of diclofenac for acute pain in children
• Allometric size models adequately explained CL and VD changes
Great Ormond Street Hospital
for Children NHS Trust
London School of Pharmacy
UCL Institute of Child Health
Centre for Paediatric Pharmacy Research
Acknowledgements
Jeff Rothwell, Rosemont Pharmaceuticals
Hussain Mulla & Brian Anderson
Anaesthetic and nursing staff at GOSH
Patients who took part
Great Ormond Street Hospital
for Children NHS Trust
London School of Pharmacy
UCL Institute of Child Health
Centre for Paediatric Pharmacy Research
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.
Great Ormond Street Hospital
for Children NHS Trust
London School of Pharmacy
UCL Institute of Child Health
Centre for Paediatric Pharmacy Research
Extra slides
Great Ormond Street Hospital
for Children NHS Trust
London School of Pharmacy
UCL Institute of Child Health
Centre for Paediatric Pharmacy Research
Individual Plots (Adults)
Great Ormond Street Hospital
for Children NHS Trust
London School of Pharmacy
UCL Institute of Child Health
Centre for Paediatric Pharmacy Research
Model Evaluation Mirror Plots (Xpose 4)
Great Ormond Street Hospital
for Children NHS Trust
London School of Pharmacy
UCL Institute of Child Health
Centre for Paediatric Pharmacy Research
Model Evaluation Mirror Plots (Xpose 4)
Great Ormond Street Hospital
for Children NHS Trust
London School of Pharmacy
UCL Institute of Child Health
Centre for Paediatric Pharmacy Research
Model Evaluation Mirror Plots (Xpose 4)
Great Ormond Street Hospital
for Children NHS Trust
London School of Pharmacy
UCL Institute of Child Health
Centre for Paediatric Pharmacy Research
CovariatesScatter Graph of Standardised Clearance Estimates
from Final Model Versus Age
0
20
40
60
80
100
120
0 5 10 15 20 25 30
Age (years)
CL
ST
D/F
(L
/hr/
70kg
)
Great Ormond Street Hospital
for Children NHS Trust
London School of Pharmacy
UCL Institute of Child Health
Centre for Paediatric Pharmacy Research
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)
VD
STD
/F (L
/70k
g)
Great Ormond Street Hospital
for Children NHS Trust
London School of Pharmacy
UCL Institute of Child Health
Centre for Paediatric Pharmacy Research
ShrinkageScatter Graph of Pooled Data: Dual Absorption Transit
Model, Observed Concentrations Versus Individual Predictions
0100020003000400050006000700080009000
0 1000 2000 3000 4000 5000 6000 7000 8000 9000
Individual predicted diclofenac concentration (nmol/L)
Ob
serv
ed d
iclo
fen
ac
con
cen
trat
ion
(n
mo
l/L)
Scatter Graph of Peadiatric Data: Dual Absorption Compartment Transit Absorption Model, Observed
Concentration Versus Individual Predictions
0100020003000400050006000700080009000
0 1000 2000 3000 4000 5000 6000 7000 8000 9000
Individual predicted diclofenac concentration (nmol/L)
Ob
serv
ed
dic
lofe
nac
co
ncen
trati
on
(n
mo
l/L
)
Pooled DV vs IPRED
Paediatric DV vs IPRED
Great Ormond Street Hospital
for Children NHS Trust
London School of Pharmacy
UCL Institute of Child Health
Centre for Paediatric Pharmacy Research
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
Great Ormond Street Hospital
for Children NHS Trust
London School of Pharmacy
UCL Institute of Child Health
Centre for Paediatric Pharmacy Research
Dose Simulations