Sven van Dijkman (1), Willem Rauwé (1), Meindert Danhof (1), Oscar Della Pasqua (1,2,3)
(1) Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, The Netherlands; (2) Clinical Pharmacology Modelling & Simulation, GlaxoSmithKline, Uxbridge, UK (3) Clinical Pharmacology and Therapeutics. University College London, 29-39 Brunswick Square London WC1N 1AX United Kingdom
Objectives: Despite numerous publications showing evidence of pharmacokinetic interaction between antiepileptic drugs (AED), this information has not been used to support the dose rationale for drug combinations.[1] In this study, we apply a model-based approach to assess the impact of drug-drug interactions on the pharmacokinetics of a variety of regimens and evaluate the need for paediatric dose adjustment when AEDs are used in combination.[2]
Methods: Population pharmacokinetic models from published literature for both children and adults were used as basis for the simulation of plasma concentrations of ten individual AEDs as well as commonly used therapeutic combinations. Pharmacokinetic profiles were simulated for a hypothetical population of adult and paediatric patients. Secondary pharmacokinetic parameters (AUC, Cmax and Cmin and their ratios in combination therapy) were subsequently used to evaluate the impact of the interaction on the resulting systemic exposure. Findings in children were compared to the results in adults, with drug levels in literature being used as reference values. R v3.1.1 was used for simulation of the demographic data, data manipulation as well as for the preparation of graphical and statistical summaries. Pharmacokinetic profiles were simulated in R v3.1.1.
Results: Hierarchical models were implemented to describe the effect of body weight and age on clearance and volume of distribution. Where available, the influence of drug combinations on clearance was also taken into account. In contrast to current practice, simulated profiles clearly show that drug-drug interactions must be characterised to allow for the use of bridging concepts and extrapolation of data from adults to children. Significant differences were found for the ratio of AUC, Cmax and Cmin in adult and paediatric population between mono- and polytherapy. Our results suggest that currently recommended dosing algorithms and titration procedures in paediatric patients do not meet bridging criteria nor ensure that appropriate therapeutic levels are achieved.
Conclusions: The use of AED combination was shown to yield significantly different average plasma concentrations, as compared to the use of single drugs. Optimisation of dosing regimen and different titration algorithms are required to ensure appropriate benefit-risk balance of the treatment, especially in the sensitive paediatric population.
References:
[1] Johannessen Landmark C, Patsalos PN. Methodologies used to identify and characterize interactions among antiepileptic drugs. Expert Rev Clin Pharmacol. 2012; 5(3):281-92.
[2] Cella M, Knibbe C, Danhof M, Della Pasqua O. What is the right dose for children? Br J Clin Pharmacol. 2010; 70(4):597-603.
Reference: PAGE 24 () Abstr 3526 [www.page-meeting.org/?abstract=3526]
Poster: Drug/Disease modeling - CNS