Andreas Matthios (1), Flora Musuamba (1) and Oscar Della Pasqua (1)
(1) University College of London
Objectives:The main objective of this analysis is to identify an exposure range for gabapentin that can be used as target for subsequent dosing recommendation in children between 3 months and 12 years old. In addition to defining the dose rationale, optimal design principles are used that allow efficient pharmacokinetic sampling in a prospective clinical trial in the paediatric population.
Methods:A nonlinear mixed effects model was developed using NONMEM v.7.2. Exposure simulations and parameter re-estimation were evaluated using a one compartment pharmacokinetic model with IIV in CL and Vd and renal function and body weight as covariates on drug disposition parameters. R was used for data analysis manipulation and graphical purposes.
Results:Covariate distribution was estimated by using literature data. The target exposure of the starting and maximum doses was estimated to be between 50 and 187 (μg.h/mL) respectively. Scenarios taking into account the role of body weight and renal function were performed to explore the starting dose and titration schedule in the paediatric population.
Conclusions: The Schwartz formula was found to efficiently replace the Cockcroft formula to describe the effects of maturation and growth on renal function in children. Moreover, our results show that the population pharmacokinetic model may be used for extrapolation purposes in children. A titration scheme is proposed to mitigate the adverse events known to occur at onset of treatment
References:
[1] Brown DL, Masselink AJ, Lalla CD. Functional range of creatinine clearance for renal drug dosing: a practical solution to the controversy of which weight to use in the Cockcroft-Gault equation. Ann Pharmacother. 2013 Jul-Aug;47(7-8):1039-44. doi: 10.1345/aph.1S176. Epub 2013 Jun 11.
[2] Schwartz, G.J., Muñoz, A., Schneider, M.F., Mak, R.H., Kaskel, F., Warady, B.A., and Furth, S.L. (2009) New Equations to Estimate GFR in Children with CKD. J Am Soc Nephrol. 20(3): 629-637.
Reference: PAGE 23 (2014) Abstr 3264 [www.page-meeting.org/?abstract=3264]
Poster: Drug/Disease modeling - Paediatrics