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| 211P London, UK Pharmacology 2016 |
Prediction of systemic drug exposure to tramadol and its active metabolite following administration of tramadol to children.
Introduction: The use of tramadol in paediatric analgesia can be controversial, as the rationale for opioid dose and dosing regimens in children has often been derived by empirical evidence. It has been licensed for use in children over 1 year of age in many European countries; however, its use has been limited to children >12 years [1]. Both tramadol and its active metabolite (o-desmethyl tramadol) bind to mu-opioid receptors. It is estimated the M1 metabolite has 200 times greater potency than tramadol in binding to the mu-opioid receptor [3]. Given its metabolic pathways, there has been concern regarding the implications for ‘ultra-fast metabolisers’, in whom the concentration can increase rapidly and lead to adverse effects; in notable cases to respiratory depression [2]. Our objective was to assess the systemic exposure to tramadol and its metabolite among paediatric populations with and without the 'ultra-rapid’ CYP2D6 phenotype variant [2].
Method: Plasma concentrations of tramadol and its metabolite in children aged 3 months to 18 years were simulated using a nonlinear, mixed effects modelling approach. Doses of 1, 2, 3, 5 and 8mg/kg were evaluated in a cohort of virtual paediatric patients. Cmax, AUC and Css were derived as parameters of interest. An existing population pharmacokinetic model by Bressole et al [4] was adapted for our simulations.
Results: Our simulations show that that Cmax depends on the dosage form and the exposure (AUC) of patients varies with age and weight, particularly within the first year. Whereas variability in drug exposure is driven primarily by the effect of body weight, clearance differences in ultra-rapid metabolisers lead to significantly higher levels of the metabolite in this subgroup of the population.
Conclusion: The clinical implications of CYP2D6 ultra-rapid phenotype in paediatric patients taking tramadol depend on the dose used. Our simulation scenarios suggest that titration procedures are essential in clinical practice when no prior knowledge is available about the metabolic phenotype of the patient.
References:
1. J. Vandenbossche, H. Clinical Pharmacology in Drug Development 2015, 4(3) 184-192.
2. Tramadol - FDA evaluating risks of using in children aged 17 and younger. August 21, 2015.
3. Marcia L. Buck. Pediatric Pharmacotherapy Volume 21 Number 10. October, 2015.
4. F. Bressolle. British Journal of Anaesthesia 102 (3): 390-9 (2009).