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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.

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Presentation on theme: "Great Ormond Street Hospital for Children NHS Trust London School of Pharmacy UCL Institute of Child Health Centre for Paediatric Pharmacy Research Developmental."— Presentation transcript:

1 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.

2 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)

3 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)

4 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)

5 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

6 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

7 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)

8 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

9 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

10 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 V D a priori Simulations to predict dose

11 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

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

13 Great Ormond Street Hospital for Children NHS Trust London School of Pharmacy UCL Institute of Child Health Centre for Paediatric Pharmacy Research Raw Data Time (hr) Graphs Showing Raw Plots of Diclofenac Serum Concentration Versus Time for Eight Adult Volunteers

14 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

15 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

16 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

17 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

18 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

19 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

20 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)

21 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

22 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

23 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

24 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

25 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

26 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 V D changes

27 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

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

30 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)

31 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)

32 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)

33 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)

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

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

36 Great Ormond Street Hospital for Children NHS Trust London School of Pharmacy UCL Institute of Child Health Centre for Paediatric Pharmacy Research Shrinkage Pooled DV vs IPRED Paediatric DV vs IPRED

37 Great Ormond Street Hospital for Children NHS Trust London School of Pharmacy UCL Institute of Child Health Centre for Paediatric Pharmacy Research Final Parameter Estimates

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


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