modelling and simulation group, school of pharmacy pharmacokinetic/pharmacodynamic understanding for...

Modelling and Simulation Group, School of Pharmacy

Pharmacokinetic/Pharmacodynamic Understanding For Fentanyl IntraNasal in the Paediatric

Population

Aaron BasingSupervisors

Prof. Carl Kirkpatrick

Dr David Herd

A/Prof. Bruce Charles

Dr Ross Norris

PUFFIN


Overview

• Why study Intranasal Fentanyl (INF) in children

• Aims and Hypothesis

• Results so far


What is INF ?

• Fentanyl that is administered via the nasal route for analgesia


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.


Medical Uses of Fentanyl

• Multiple clinical applications

– Anaesthesia• Induction• Maintenance

– Analgesia• Acute• Chronic


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.


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


Why do we need INF ?

• Viable alternative to intravenous analgesia

– Needleless

– Rapid Absorption

– Sterile technique not

required


What we already know about INF

• It is effective

IV morphine 0.1mg/kgINF 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.


What we already know about INF

• It can reduce time to analgesia


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


What we DON’T know about INF

• The underlying pharmacokinetics for INF in the paediatric population


What we don’t know about

• Dosing strategies have been developed empirically from adult pharmacokinetic studies

Potential for therapeutic catastrophe


Pharmacokinetics of Fentanyl

• ABSORPTION

• DISTRIBUTION

• METABOLISM

• EXCRETION


Pharmacokinetics in Adults

ABSORPTION

– Rapid, Tmax approx 10 minutes

– Bioavailablity – 70-90%

Drug Administration

Drug in Blood Stream


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



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



EXCRETION

• Kidney– 10% Unchanged

• Faeces– 1% Unchanged

Drug in Blood Stream

Drug outside of body


What we need to know INF

• Guestimate of pharmacokinetic parameters in paediatrics compared to adults

– Clearance ? ↓

– Volume of Distribution ? ↓

– Nasal absorption rate constant ???? ↑↓


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.


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


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


AIMS

• What we hope to achieve


AIM 1

• Determine if varying techniques for the preparation and administration of intranasal fentanyl effect the amount of drug delivered


AIM 2

• Using optimal design methodologies, design a trial protocol to study the population pharmacokinetics of intranasal fentanyl in paediatric patients


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.


AIM 5

• Perform simulations to answer clinically relevant questions for the treatment of acute or procedural pain in paediatric patients by INF


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


Results so far

• However we do have • Adult INF studies

• Expolate using a linear relationship between weight and dose


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.



• Allometric Scaling


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.



• Maturation Function

Sumpter, A. and B. J. Anderson (2009). "Pediatric pharmacology in the first year of life." Curr Opin Anaesthesiol 22(4): 469-475.


Putting it all together


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???


Other significant milestones

• Review paper of Transmucosal opiates in paediatrics in progress

• Competency in Assay Technique LC MS/MS


What still needs to do be done


Acknowledgements

• Supervisors

• ACPP Laboratory staff

• Mater Children’s Emergency Department

• QUM and Medical Students

• QEMRF

• Modelling and simulation group members


QUESTIONS

?

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