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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. 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

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  1. Developmental Pharmacokinetics of Diclofenac for Acute Pain Standing JF, Howard RF, Johnston A, Savage I, Wong ICK.

  2. 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)

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

  4. Diclofenac Pharmacodynamics (McQuay 1998)

  5. Diclofenac Pharmacodynamics NNT for 50% pain relief Diclofenac dose (mg) (McQuay 1998)

  6. Diclofenac Pharmacodynamics In children: (Romsing 1997)  pain scores  opioid requirements  paracetamol requirements

  7. Paediatric Dosing • 0.5mg/kg (Tay 2002) • 1mg/kg (Mendham 1996) • 2mg/kg (Nishina 2000) • 2.5mg/kg (McGowan 1998)

  8. Overview • Introduction • Aims/Methods • Results • Model Evaluation • Dose Simulations • Conclusions

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

  10. 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

  11. 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

  12. Raw Data

  13. Graphs Showing Raw Plots of Diclofenac Serum Concentration Versus Time for Eight Adult Volunteers Time (hr) Raw Data

  14. Structural Model Building • One compartment • Two compartment • Dual absorption one compartment • Dual absorption two compartment

  15. Final Structural Model

  16. Model Evaluation IPRED vs DV

  17. Model Evaluation WRES vs Time

  18. Model Evaluation • Mainly focussed on simulated data from model • Shrinkage

  19. Model Evaluation Visual Predictive Check

  20. Model Evaluation Mirror Plots (Xpose 4)

  21. 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

  22. 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

  23. Overview • Introduction • Aims/Methods • Results • Model Evaluation • Dose Simulations • Conclusions

  24. Simulations • Dose levels: • 0.5mg/kg • 1mg/kg • 1.5mg/kg • 2mg/kg • AUC ratio: • Child AUC: Adult 50mg AUC

  25. 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

  26. Conclusions • 1mg/kg optimum dose of diclofenac for acute pain in children • Allometric size models adequately explained CL and VD changes

  27. Acknowledgements Jeff Rothwell, Rosemont Pharmaceuticals Hussain Mulla & Brian Anderson Anaesthetic and nursing staff at GOSH Patients who took part

  28. 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.

  29. Extra slides

  30. Individual Plots (Adults)

  31. Model Evaluation Mirror Plots (Xpose 4)

  32. Model Evaluation Mirror Plots (Xpose 4)

  33. Model Evaluation Mirror Plots (Xpose 4)

  34. Covariates

  35. Covariates

  36. Shrinkage Pooled DV vs IPRED Paediatric DV vs IPRED

  37. Final Parameter Estimates

  38. Dose Simulations

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