Impact of metabolic polymorphism on the exposure to tramadol and its active metabolite in children
Paul Healy, Oscar Della Pasqua
Clinical Pharmacology & Therapeutics Group, University College London, London, UK
Objectives: It is estimated the M1 metabolite has 6 times greater analgesic potency than tramadol [1]. Patients with ‘ultra-rapid’, metabolising function of the CYP2D6 enzyme are more susceptible to adverse effects, notably respiratory depression [2], as the concentration of M1 metabolite increases rapidly. The objective of the current investigation is to demonstrate the relevance of clinical trial simulations as a tool for the evaluation of the systemic exposure to tramadol and its metabolite in paediatric populations and explore the potential clinical implications of CYP2D6 phenotype variants, focusing on UR-metabolisers [2].
Methods: A population pharmacokinetic model by Bressole et al [3] was adapted for the purpose of our analysis. This model was developed using data from children (1–8 years), who were given tramadol by continuous infusion. Given the use of intravenous route, estimates were obtained for absolute clearance (14.7 L/hr) and volume of distribution (8.01 L). The model was combined with estimates of the absorption rate constant observed after administration of an oral formulation using data from Payne et al [5]. When simulating the effect of metabolic polymorphism in clearance, the dataset was expanded to patients with ages from 3 months to 18 years. In addition to the time course of drug levels in plasma, Cmax, AUC, Css as well the ratio between parent drug and metabolite were derived as parameters of interest.
Results: A two-compartment model with absorption rate constant of 0.83 min-1 best described the PK of tramadol and M1. The clearance values differed substantially between extensive (0.361 L/hr) and UR-metabolisers (0.843 L/hr). Simulated profiles showed that Cmax depends on the dosage form, and the exposure (AUC) varies with age and weight. Whereas variability in drug exposure is driven primarily by the effect of body weight, clearance in fast metabolisers leads to significantly higher levels of the metabolite in this subgroup of the population.
Conclusions: The clinical implications of CYP2D6 ultra-rapid phenotype in paediatric patients taking tramadol ultimately depends on the dose and formulation used at the onset of treatment. The proposed simulation scenarios suggest that titration procedures are essential in clinical practice when no prior knowledge is available about the metabolic phenotype of individual patients.
References:
[1] Marcia L. Buck. Pediatric Pharmacotherapy, Volume 21 Number 10. October, 2015.
[2] Tramadol – FDA evaluating risks of using in children aged 17 and younger. August 21, 2015.
[3] F. Bressolle. British Journal of Anaesthesia, 102 (3): 390–9 (2009).
[4] J. Vandenbossche, H. Richards, B. Solanki, and A. Van Peer. Single- and Multiple-Dose Pharmacokinetic Studies of Tramadol Immediate-Release Tablets in Children and Adolescents. Clinical Pharmacology in Drug Development, 4(3) 184–192, 2015.
[5] K. A. Payne. Pharmacokinetics of Oral Tramadol Drops for Postoperative Pain Relief in Children Aged 4 to 7 Years. American Dental Society of Anesthesiology, 2002.