developmental pharmacokinetics of diclofenac for acute pain
Download
Skip this Video
Download Presentation
Developmental Pharmacokinetics of Diclofenac for Acute Pain

Loading in 2 Seconds...

play fullscreen
1 / 38

developmental pharmacokinetics of diclofenac for acute pain - PowerPoint PPT Presentation


  • 256 Views
  • Uploaded on

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)

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'developmental pharmacokinetics of diclofenac for acute pain' - Antony


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
developmental pharmacokinetics of diclofenac for acute pain
Developmental Pharmacokinetics of Diclofenac for Acute Pain

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

diclofenac
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
Diclofenac
  • Most common “off-label”(Turner 1998)
diclofenac pharmacodynamics5
Diclofenac Pharmacodynamics

NNT for 50% pain relief

Diclofenac dose (mg)

(McQuay 1998)

diclofenac pharmacodynamics6
Diclofenac Pharmacodynamics

In children: (Romsing 1997)

 pain scores

 opioid requirements

 paracetamol requirements

paediatric dosing
Paediatric Dosing
  • 0.5mg/kg (Tay 2002)
  • 1mg/kg (Mendham 1996)
  • 2mg/kg (Nishina 2000)
  • 2.5mg/kg (McGowan 1998)
overview
Overview
  • Introduction
  • Aims/Methods
  • Results
  • Model Evaluation
  • Dose Simulations
  • Conclusions
slide9
Aim

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

method
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
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

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

Time (hr)

Raw Data
structural model building
Structural Model Building
  • One compartment
  • Two compartment
  • Dual absorption one compartment
  • Dual absorption two compartment
model evaluation
Model Evaluation
  • Mainly focussed on simulated data from model
  • Shrinkage
model evaluation predictive check
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
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
overview23
Overview
  • Introduction
  • Aims/Methods
  • Results
  • Model Evaluation
  • Dose Simulations
  • Conclusions
simulations
Simulations
  • Dose levels:
    • 0.5mg/kg
    • 1mg/kg
    • 1.5mg/kg
    • 2mg/kg
  • AUC ratio:
    • Child AUC: Adult 50mg AUC
dose simulations
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
Conclusions
  • 1mg/kg optimum dose of diclofenac for acute pain in children
  • Allometric size models adequately explained CL and VD changes
acknowledgements
Acknowledgements

Jeff Rothwell, Rosemont Pharmaceuticals

Hussain Mulla & Brian Anderson

Anaesthetic and nursing staff at GOSH

Patients who took part

references
References

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.

shrinkage
Shrinkage

Pooled DV vs IPRED

Paediatric DV vs IPRED

ad