1. Modelling and Simulation Group, School of Pharmacy Pharmacokinetic/Pharmacodynamic Understanding For Fentanyl IntraNasal in the Paediatric Population Aaron Basing Supervisors Prof. Carl Kirkpatrick Dr David Herd A/Prof. Bruce Charles Dr Ross Norris PUFFIN

2. Modelling and Simulation Group, School of Pharmacy Overview Why study Intranasal Fentanyl (INF) in children Aims and Hypothesis Results so far

3. Modelling and Simulation Group, School of Pharmacy What is INF ? Fentanyl that is administered via the nasal route for analgesia

4. Modelling and Simulation Group, School of Pharmacy Fentanyl Micovic, I. V., M. D. Ivanovic, et al. (2000). "The synthesis and preliminary pharmacological evaluation of 4-methyl fentanyl." Bioorganic & medicinal chemistry letters 10(17): 2011-2014.

5. Modelling and Simulation Group, School of Pharmacy Medical Uses of Fentanyl Multiple clinical applications –Anaesthesia Induction Maintenance –Analgesia Acute Chronic

6. Modelling and Simulation Group, School of Pharmacy Clinical Context Paediatric Emergency Room –Painful injuries are common  –Painful procedures are common Most frequent diagnoses of paediatric ED patients at PREDICT sites (n = 314 025 presentations at nine sites) 2 Acworth, J., F. Babl, et al. (2009). "Patterns of presentation to the Australian and New Zealand Paediatric Emergency Research Network." Emergency medicine Australasia : EMA 21(1): 59-66.

7. Modelling and Simulation Group, School of Pharmacy Clinical Context Pain in the emergency department is poorly treated –Oligoanalgesia –Delay in time to analgesia Todd, K. H., J. Ducharme, et al. (2007). "Pain in the emergency department: results of the pain and emergency medicine initiative (PEMI) multicenter study." The journal of pain : official journal of the American Pain Society 8(6): 460-466. N = 842

8. Modelling and Simulation Group, School of Pharmacy Why do we need INF ? Viable alternative to intravenous analgesia –Needleless –Rapid Absorption –Sterile technique not required

9. Modelling and Simulation Group, School of Pharmacy What we already know about INF It is effective IV morphine 0.1mg/kg INF 1.4 µg/kg Borland, M., I. Jacobs, et al. (2007). "A randomized controlled trial comparing intranasal fentanyl to intravenous morphine for managing acute pain in children in the emergency department." Ann Emerg Med 49(3): 335-340.

10. Modelling and Simulation Group, School of Pharmacy What we already know about INF It can reduce time to analgesia

11. Modelling and Simulation Group, School of Pharmacy Summary so far Painful injuries and procedures are common in paediatric emergency departments. INF has several features that are well suited to use within a paediatric emergency department

12. Modelling and Simulation Group, School of Pharmacy What we DON’T know about INF The underlying pharmacokinetics for INF in the paediatric population

13. Modelling and Simulation Group, School of Pharmacy What we don’t know about Dosing strategies have been developed empirically from adult pharmacokinetic studies  Potential for therapeutic catastrophe

14. Modelling and Simulation Group, School of Pharmacy Pharmacokinetics of Fentanyl ABSORPTION DISTRIBUTION METABOLISM EXCRETION

15. Modelling and Simulation Group, School of Pharmacy Pharmacokinetics in Adults ABSORPTION –Rapid, T max approx 10 minutes –Bioavailablity – 70-90% Drug Administration Drug in Blood Stream

16. Modelling and Simulation Group, School of Pharmacy What we know about the pharmacokinetics of fentanyl DISTRIBUTION –Octanol/Water Coefficient 9550 –Adipose Tissue – some –Skeletal muscle – some –Well Perfused organs – High Drug in Blood Stream Body Tissue

17. Modelling and Simulation Group, School of Pharmacy What we know about the pharmacokinetics of fentanyl METABOLISM Primarily N-Dealkylation to norfentanyl (inactive) by CYP3A4 Large variability in clearance –Genetic variability in CYP3A4 –Physiologic and pathophysiologic variability in liver blood flow Drug in Blood Stream Metabolites

18. Modelling and Simulation Group, School of Pharmacy What we know about the pharmacokinetics of fentanyl EXCRETION Kidney –10% Unchanged Faeces –1% Unchanged Drug in Blood Stream Drug outside of body

19. Modelling and Simulation Group, School of Pharmacy What we need to know INF Guestimate of pharmacokinetic parameters in paediatrics compared to adults –Clearance ? ↓ –Volume of Distribution ? ↓ –Nasal absorption rate constant ???? ↑↓

20. Modelling and Simulation Group, School of Pharmacy Why is this particularly important Fentanyl has serious side effects B. Yassen, A., J. Kan, et al. (2006). "Mechanism-based pharmacokinetic-pharmacodynamic modeling of the respiratory-depressant effect of buprenorphine and fentanyl in rats." J Pharmacol Exp Ther 319(2): 682-692.

21. Modelling and Simulation Group, School of Pharmacy Why is this important Besides dosage other relevant clinical questions remain to be answered with science rather than anecdote –When should it start to work –When is it safe to re-dose

22. Modelling and Simulation Group, School of Pharmacy How we will determine the parameters of interest Population PK/PD modelling allows: –Optimal design data –Estimation of variability and affect of covariates –Allows “what if” experiments to be completed in silico

23. Modelling and Simulation Group, School of Pharmacy AIMS What we hope to achieve

24. Modelling and Simulation Group, School of Pharmacy AIM 1 Determine if varying techniques for the preparation and administration of intranasal fentanyl effect the amount of drug delivered

25. Modelling and Simulation Group, School of Pharmacy AIM 2 Using optimal design methodologies, design a trial protocol to study the population pharmacokinetics of intranasal fentanyl in paediatric patients

26. Modelling and Simulation Group, School of Pharmacy AIM 3 + 4 Determine the most appropriate model to describe the relationship between administered dose of intranasal fentanyl and observed blood concentration in paediatric patients. Determine the most appropriate model to describe the relationship between blood concentration of fentanyl and pain score after administration of intranasal fentanyl to the paediatric population.

27. Modelling and Simulation Group, School of Pharmacy AIM 5 Perform simulations to answer clinically relevant questions for the treatment of acute or procedural pain in paediatric patients by INF

28. Modelling and Simulation Group, School of Pharmacy Results so far For statistical optimisation of a trial design we must have some idea of the underlying model –Problem!!! No studies report the pharmacokinetics of INF in children

29. Modelling and Simulation Group, School of Pharmacy Results so far However we do have Adult INF studies Expolate using a linear relationship between weight and dose

30. Modelling and Simulation Group, School of Pharmacy How do we use adult data This is not a linear relationship Gillooly, J. F., J. H. Brown, et al. (2001). "Effects of size and temperature on metabolic rate." Science 293(5538): 2248-2251.

31. Modelling and Simulation Group, School of Pharmacy How do we use adult data Allometric Scaling

32. Modelling and Simulation Group, School of Pharmacy Allometry doesn’t explain it all Anderson, B. J. and N. H. Holford (2009). "Mechanistic basis of using body size and maturation to predict clearance in humans." Drug Metab Pharmacokinet 24(1): 25-36.

33. Modelling and Simulation Group, School of Pharmacy How do we use adult data Maturation Function Sumpter, A. and B. J. Anderson (2009). "Pediatric pharmacology in the first year of life." Curr Opin Anaesthesiol 22(4): 469-475.

34. Modelling and Simulation Group, School of Pharmacy Putting it all together

35. Modelling and Simulation Group, School of Pharmacy Sampling times and windows Run competing maturation models and varying allometric exponents for varying age.  Database of different sampling times for different ages  Do the sampling windows overlap???

36. Modelling and Simulation Group, School of Pharmacy Other significant milestones Review paper of Transmucosal opiates in paediatrics in progress Competency in Assay Technique LC MS/MS

37. Modelling and Simulation Group, School of Pharmacy What still needs to do be done

38. Modelling and Simulation Group, School of Pharmacy Acknowledgements Supervisors ACPP Laboratory staff Mater Children’s Emergency Department QUM and Medical Students QEMRF Modelling and simulation group members

39. Modelling and Simulation Group, School of Pharmacy QUESTIONS ?

40. Modelling and Simulation Group, School of Pharmacy