2007 - København - Denmark

PAGE 2007: Applications
Joe Standing

Developmental Pharmacokinetics of Diclofenac for Acute Pain

JF Standing (1,2), RF Howard (1,3), A Johnston (4), I Savage (2), ICK Wong (1,2,3)

(1) Great Ormond Street Hospital for Children, London, UK; (2) School of Pharmacy, University of London, UK; (3) Institute of Child Health, University College London, UK; (4) St George’s Medical School, University of London, UK.

Introduction: Diclofenac is an effective, opiate-sparing analgesic widely used for peri-operative pain in children [1] with single doses of 0.5-2mg/kg being used in clinical practice.  Although no concentration/effect relationship has been ascertained, adult pharmacodynamic studies have shown a ceiling effect above 50mg [2].  Diclofenac's main therapeutic action is cyclooxygenase-2 (COX-2) inhibition, which occurs in a time-dependent manner in vitro [3]. There is no licensed paediatric oral formulation, and little published pharmacokinetic data in children.

Objectives: Investigate the ontogeny of diclofenac pharmacokinetics; recommend a suitable paediatric dose to achieve an equivalent effect of 50mg in adults.

Methods: Rich pharmacokinetic data in 30 adults given a 50mg dose was provided by the manufacturer of a new diclofenac oral suspension. A clinical pharmacokinetic study was carried out on a paediatric day-surgery ward.  Before surgery each child (age 1-12y) was given a 1mg/kg dose by oral syringe.  Serum samples were drawn on induction of anaesthesia, at the end of surgery and on removal of the venous cannula.  A digital watch was provided to each child, by which dosing and blood sampling times were recorded. 

Pooled adult and paediatric pharmacokinetic modelling was undertaken in NONMEM (version VI) using first-order conditional estimation with interaction.  The absorption phase was modelled using single and dual absorption compartments, with combinations of first, zero, mixed first and zero, and transit absorption models [4] tested.  Residual error was modelled separately for adult and paediatric data, assays having been performed in different laboratories.  The final model was evaluated using predictive checks.  Simulations were performed to predict paediatric dosing which gave similar exposure (AUC) to 50mg in adults, the rationale for this being that this is an effective dose in adults, the assumption that COX-2 concentration at the site of tissue injury is not developmentally different, and that enzyme drug exposure is important for analgesia [3].

Results and Discussion:  A total of 558 serum diclofenac concentrations from 100 (70 paediatric, 30 adult, weight range 9-93kg) patients were used in the pooled analysis.  Double peaks seen in raw plots were probably due to pH dependent diclofenac dissolution from solid particles in suspension.  A one compartment model with dual absorption compartments was chosen.  Allometric scaling of CL (wt^0.75) and VD (wt) [5] was added prospectively as part of the structural model in an attempt to delineate body size with age-related maturational variability.  Geometric mean standardised CL of 52.9, 50.8 and 50.4 L/hr/70kg were estimated for patients aged 1-3, 4-12 and adults respectively, showing the allometric model adequately explains variations in diclofenac CL with age.  This was confirmed by covariate analysis where there were no further significant influences on CL or VD.  Allometric scaling is based on the observation that basal metabolic rate scales with wt^0.75 across species [6].  It must be noted the proposition that basal metabolic rate scales with wt^0.75 cannot be tested in humans (i.e. within a species) as a 9-fold adult weight range would be required to see significant differences with other proposed scaling factors such as wt^0.67 [6].  In this study wt^0.75 reasonably explained changes in diclofenac CL with size; it is envisaged future work will lead to a time when children can be considered ‘small adults' in terms of drug dosing.    

Of the simulated doses investigated, 1mg/kg gave paediatric AUC values divided by adult 50mg AUC ratios of 1.00, 1.08 and 1.18 for ages 1-3, 4-6 and 7-12 respectively.  Dosing with body weight in a linear (1mg/kg) fashion produces almost a 20% difference in exposure between infants and children aged 7-12, which for diclofenac is unlikely to prove clinically significant either in terms of analgesia or adverse effects. 

Conclusions: The allometric wt^0.75 model adequately explained variability in CL with age for diclofenac, which may indicate maturation of diclofenac ADME is complete by 1 year.  This study has shown 1mg/kg to produce similar exposure in infants and children up to 12 years to 50mg in adults, and is acceptable for clinical practice; patients are unlikely to obtain further benefit from 2mg/kg.  It must be noted that dosing in a linear fashion will lead to higher exposure in older children, which is unlikely to be of clinical significance for diclofenac, but could be for drugs with a narrower therapeutic index.  Future work will investigate the influence of age and CYP2C9 genotype on the clearance of diclofenac to 4'-hydroxydiclofenac; and broader research on the development of a ‘paediatric delineation factor'.

[1] 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.
[2] 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.
[3] 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.
[4] 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.
[5] 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.
[6] Kleiber M. 1947. Body size and metabolic rate. Physiological Reviews, 27: 511-41.

Acknowledgements: Brian Anderson and Hussain Mulla gave invaluable advice on pharmacokinetic modelling, Rada Savic kindly provided code for transit absorption model.  Funding was from Rosemont Pharmaceuticals Ltd, UK.

Reference: PAGE 16 (2007) Abstr 1086 [www.page-meeting.org/?abstract=1086]
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