Background Gabapentin and tramadol are drugs com-monly used in various treatment of pain in adults. Gab-apentin has been successfully given for neuropathic pain and has been used off-label to treat children with the same condition. Tramadol has been licensed for the use in children older than 1 month in some European coun-tries, but its use has been limited to children>12 years. The management of chronic pain in paediatric patients is burdened by the insufficiency of clinical information, therefore, in order to investigate appropriate dosing for this population, pharmacokinetic (PK) modelling and simulation of virtual patient groups is a most useful ap-proach. In this study we report the analyses used to characterise the population PK and corresponding hier-archical models that are required to provide an adequate description of the time course and variability of drug con-centrations in plasma.
Methods Non-linear, mixed-effect modelling was used to simulate the plasma concentrations of gabapentin and tramadol in subjects between the ages of 3 months and 18 years, under the assumption of comparable ex-posure-response relationships in adult and paediatric patients. Previously published PK models in paediatric pa-tients by Ouellet et al1 and Garrido et al2 were chosen and adapted for gabapentin and tramadol, respectively. Dosing regimens for both drugs were evaluated in a co-hort of virtual patients, based upon off-label doses used empirically. The population for the simulations was con-structed using data from the NHANES database; individu-al body weight was the primary covariate factor affecting PK disposition. The exposure (AUC) and Cmax parameters were derived from the simulated plasma concentrations, to compare with efficacious adult levels. Both drugs are titrated to a maximum dose over a period of 3 weeks, giv-en three times daily.
Results The desired exposure in children should be comparable to the median value obtained for area under the concentration vs. time curve at steady state. An adult AUC range of 25 mg/L*h to 75 mg/L*h corresponded to gabapentin dosing at 63 mg/kg/day and 45 mg/kg/day in patients weighing 5–15 kg and >15 kg, respectively (after a three week titration). Mean plasma concentrations of between 200–300 ng/mL were chosen as a target level for tramadol, and a titration scheme over a three week period up to a maximum of 8 mg/kg/day proceeded to achieve safe dosing. At the end of the titration phase, all weight groups showed drug exposure in the range shown to be safe and effective for the proposed regimens.
Conclusion Clinical trial simulations showed how the proposed dosing regimens yielded suitable drug expo-sure in paediatric populations, suggesting a solution to the issue of under-or over-dosing in this subgroup, and informing appropriate dosage information. This informa-tion contributes to avoiding unnecessary adverse events or, conversely, ineffective treatment.
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