Irina Bondareva
The Research Institute of Physical – Chemical Medicine, Russia
Objectives: Epilepsy is a chronic disease requiring long term treatment with antiepileptic drugs (AEDs). While monotherapy is considered as the gold standard, patients who don’t respond are prescribed AED polytherapy. So called old AEDs are involved in many interactions due to their pharmacokinetic (PK) properties. Although the PK interactions are well documented in general, their magnitude varies among studies. The objective of the study is to evaluate changes in the CBZ population PK due to AED interactions and to develop a nonlinear model describing CBZ heteroinduction when another AED is added to a CBZ monotherapy from repeated TDM data.
Methods: TDM data were routinely collected in the Laboratory of Pharmacokinetics of Moscow Medical University. Levels of anticonvulsants were measured by high performance liquid chromatography. The nonparametric population PK analysis was performed using the USC*PACK software based on 460 TDM (peak-trough strategy) data files of adult epileptic patients who received chronic CBZ-monotherapy or duotherapy. In the nonlinear model of CBZ heteroinduction, the metabolic rate of elimination asymptotically changes from a monotherapy value (D) during time-lag (Lamda) to a value (D+A) after heteroinduction. The model was fitted by the NPEM to the multiple TDM data of 24 patients for whom measured CBZ levels related to both CBZ-mono and polytherapy.
Results: The steady-state CBZ- monotherapy half-lives were estimated as 3.2 – 50.6h (median = 10h) using a one-compartment model and TDM data of 100 adult epileptic patients. Great interindividual variability of CBZ PK for both mono- and polytherapy was observed (70 – 95% for the metabolic rate). Heteroinduction effects of CBZ metabolism by phenytoin and phenobarbital were clearly demonstrated. The lack of significant influence of valproate on CBZ total levels was obtained. The population parameter estimates are in good agreement with those reported in the literature. Individual serum CBZ level/dose ratios in patients taking CBZ plus AED were changed compared to the CBZ alone values.
Conclusions: The study demonstrated wide inter- and intraindividual variability of CBZ pharmacokinetics due to AED interactions and, taking into consideration narrow therapeutic range, the need for individualizing when an AED is added to a pre-existing AED regimen. Estimation of individual PK parameters might help to optimize CBZ polytherapy in epileptic patients based on thoughtful TDM data.
Reference: PAGE 24 () Abstr 3485 [www.page-meeting.org/?abstract=3485]
Poster: Drug/Disease modeling - CNS