pharma gel slide
TRANSCRIPT
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DevelopmentalPharmacokinetics of
Diclofenac for Acute Pain
Standing JF, Howard RF, Johnston A,
Savage I, Wong ICK.
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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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Diclofenac Pharmacodynamics
(McQuay 1998)Diclofenac dose (mg)
NNT for 50%pain relief
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Diclofenac Pharmacodynamics
In children: (Romsing 1997)
pain scores opioid requirements paracetamol requirements
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Paediatric Dosing
0.5mg/kg (Tay 2002)
1mg/kg (Mendham 1996)
2mg/kg (Nishina 2000)
2.5mg/kg (McGowan 1998)
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Overview
Introduction
Aims/Methods
Results Model Evaluation
Dose Simulations
Conclusions
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Aim
Predict a paediatric dose
which gives a similar AUC to
50mg in adults
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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
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Time (hr)
Diclofenacserum
concentration(nmol/L)
Adult volunteers
Paediatric Patients
Scatter Graph of Raw Diclofenac Concentrations Versus
Time
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Time (hr)
Diclofenacserum
concentration(nmol/L)
Adult volunteers
Paediatric Patients
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Raw Data
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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
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Individual predicted diclofenac concentration (nmol/L)
Observeddiclofenac
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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Time (hr)
Weig
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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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Time (hr)
Diclofenacs
erumconcentration(nm
ol/L)
Median
95th Percentile
5th Percentile
Raw Data
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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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Paediatric
Pharmacy
Research
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
Mirror Plots (Xpose 4)
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Mirror Plots (Xpose 4)
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Model Evaluation
Mirror Plots (Xpose 4)
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Covariates
Scatter Graph of Standardised Clearance Estimatesfrom Final Model Versus Age
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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
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Age (years)
VDSTD/F
(L/70kg)
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ShrinkageScatter Graph of Pooled Data: Dual Absorption Transit
Model, Observed Concentrations Versus Individual
Predictions
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9000
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Individual predicted diclofenac concentration (nmol/L)
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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Individual predicted diclofenac concentration (nmol/L)
Observeddiclofenac
concentration(nmol/L)
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