Sven van Dijkman (1), Meindert Danhof (1), Oscar Della Pasqua (1,2)
(1) Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, The Netherlands; (2) Clinical Pharmacology Modelling & Simulation, GlaxoSmithKline, Uxbridge, UK
Objectives: Despite the wide number of publications on the pharmacokinetics of antiepileptic drug combinations, drug-drug interactions have not been accurately characterised in children, resulting in unclear dose rationale. In this study, we aim to use a model-based approach to characterise AED concentrations following a variety of regimens with Valproic Acid (VPA), Carbamazepine (CBZ) and Phenytoin (PHT) and explore the impact of developmental growth on systemic exposure. The resulting models will later be used to simulate concentrations for patients in another dataset with outcome data where only dose was recorded, to be able to more accurately quantify the concentration-effect relationships for these drugs.
Methods: Population pharmacokinetic models [1, 2, 3] from published literature were used as basis for the simulation of plasma concentration of individual drugs as well as combined therapy [4, 5]. PK profiles were generated for a cohort of children from 03 months to 16 years of age to assess the magnitude of the interaction between developmental growth and drug-induced changes in metabolic clearance on the resulting systemic exposure. AUC, Cmax and Cmin and their ratios in combination therapy were derived as parameters of interest. Results were then compared to drug levels in adults. Simulations were performed in NONMEM v7.2. R was used for data manipulation, graphical and statistical summaries.
Results: Allometric models were implemented to describe the effects of body weight and metabolic maturation on clearance and volume of distribution. In contrast to current practice, simulated profiles clearly show that drug-drug interactions must be taken into account to ensure comparable exposure in children and adults. Significant differences were found for the ratio of AUC, Cmax and Cmin in adult and paediatric population. Our results indicate that currently recommended dosing algorithms and titration procedures do not warrant maintenance of the appropriate therapeutic levels of AEDs in children.
Conclusions: Phenytoin when combined with carbamazepine or valproic acid significantly alters the average plasma concentrations of these drugs. Dosing regimen and titration in children need therefore to account for such interactions. A model-based algorithm can provide the basis for improved dosing regimen, especially in very young children.
References:
[1] Correa T, RodrÃguez I, Romano S. Population pharmacokinetics of valproate in Mexican children with epilepsy. Biopharm Drug Dispos. 2008 Dec;29(9):511-20. doi: 10.1002/bdd.636.
[2] Al Za’abi M, Lanner A, Xiaonian X, Donovan T, Charles B. Application of routine monitoring data for determination of the population pharmacokinetics and enteral bioavailability of phenytoin in neonates and infants with seizures. Ther Drug Monit. 2006 Dec;28(6):793-9.
[3] El Desoky ES, Sabarinath SN, Hamdi MM, Bewernitz M, Derendorf H. Population pharmacokinetics of steady-state carbamazepine in Egyptian epilepsy patients. J Clin Pharm Ther. 2012 Jun;37(3):352-5. doi: 10.1111/j.1365-2710.2011.01296.x. Epub 2011 Aug 23.
[4] Gray AL, Botha JH, Miller R. A model for the determination of carbamazepine clearance in children on mono- and polytherapy. Eur J Clin Pharmacol. 1998 Jun;54(4):359-62.
[5] Sirmagul B et al. (2012) The effect of combination therapy on the plasma concentrations of traditional antiepileptics: a retrospective study. Hum Exp Toxicol. 31:971-80.
Reference: PAGE 22 (2013) Abstr 2863 [www.page-meeting.org/?abstract=2863]
Poster: Paediatrics