Establishing the dose rationale for gabapentin, tramadol and morphine in paediatric chronic pain

A Matthios, F Musuamba, O Pasqua. UCL, London, UK

Although different guidelines suggest the pharmacological treatment of chronic pain in children, pain management is often inappropriate. GAPP, an FP7 funded project, aims to develop an oral liquid formulation of gabapentin for children. A clinical study is planned to demonstrate the efficacy and safety of this new formulation, as compared to tramadol and morphine in moderate and severe neuropathic pain respectively. The aim of this study is to define the dose rationale for the use of these three drugs (gabapentin, tramadol and morphine) in a prospective clinical trial in paediatric pain. Using a model-based approach, in conjunction with clinical pharmacokinetic literature data, we have simulated pharmacokinetic profiles to establish the therapeutic exposure of the drugs in adults. Additionally, by applying a bridging strategy, dose levels were derived for a paediatric target population in such a way that comparable exposures could be achieved across the two populations. The pharmacokinetic models used in the analysis were extracted from publications by Ouellet et al., 2001, for gabapentin, by Bressolle et al., 2009, for tramadol and by Wang C, 2013 for morphine. Simulations where performed in one hundred patients one hundred times. AUC, Cmax and Css were the matrix of interest. For gabapentin the therapeutic drug concentrations weren't available in the literature. The maximum and the minimum doses in adults were used to identify the target exposure of gabapentin which was assumed to also be applicable to children. A previously published PK model in adults was used for that purpose (Lal et al., 2013). In order to identify the starting dose and the titration rate in the paediatric population the pharmacokinetic model in children was modified and covariates such as body weight, height and serum creatinine were introduced in the model. Plasma concentrations of tramadol between 200-300ng/ml are known to be associated with an adequate control of pain (Garrido MJ et al., 2006). Absorption-related parameters such as bioavailability (68%) and absorption rate constant (ka=2.8) were taken from another model (Payne et al., 2002). Morphine’s bioavailability (F=23.9%) and absorption rate constant (ka=0.3) were taken from another model (Hunt et al.,1999). Simulations were conducted in order to identify the exposure levels reached with different dosing regimens and pharmaceutical formulations. A modelling and simulation framework was proposed for dose rationale in prospective clinical trials in paediatric pain. The framework was adapted to the available information for each of the drugs.

Table 1: Starting dose of gabapentin per body weight