Irina Bondareva (1), Abrek Sariev (2) and Denis Abaimov (2)
(1) The Research Institute of Physical – Chemical Medicine, Russia, (2) The Research Center of Neurology, Russian Academy of Medical Science, Russia
Objectives: CBZ is one of the most widely used antiepiletptic drugs for the treatment of partial and tonic-clonic seizures. Its main metabolite CBZ-10,11-epoxide is known to have antiepileptic properties similar to those of CBZ itself. The objective of the study is to develop a model of CBZ and its main metabolite (CBZE) pharmacokinetics (PK) and to estimate the model parameters from TDM data of adult epileptic patients on chronic CBZ – monotherapy.
Methods: Patient data of CBZ and CBZE monitoring were routinely collected in the Department of Pharmacokinetics of the Research Center of Neurology, Russian Academy of Medical Science. CBZ and CBZE levels were simultaneously measured by gas – chromatography – mass spectrometry. The assay error pattern was used as: SD=0.1+0.1C (where SD is standard deviation of the assay at measured concentration C). The nonparametric population PK analysis was performed using the Pmetrics based on a compartmental model with first-order absorption and linear elimination kinetics for both CBZ and CBZE. This study included 52 patients (40.8±14.3 years) for whom at least one pair of two measured serum levels of CBZ and CBZE (peak – trough strategy) related to CBZ dosage was available.
Results: Great interindividual variability of both CBZ and CBZE level to daily dose ratios was observed. Serum CBZE concentrations were 8 – 35% those of the parent drug. The CBZ:CBZ ratio increased for peak versus trough concentrations (the mean difference = 1.4%, p=0.03). The interindividual variability of CBZE:CBZ concentration ratio was estimated as 46%. The estimated CBZ and CBZE population PK parameter values were in good agreement with those obtained earlier for the steady-state CBZ population PK model for epileptic adult patients [1].
Conclusions: The study demonstrated wide interindividual variability in CBZ and CBZE pharmacokinetics and the need for individualizing of CBZ dosage regimens. Estimation of individual PK parameters of both drug and its active metabolite might help to optimize CBZ therapy in epileptic patients based on TDM data.
References:
[1] Bondareva I.B., Sokolov A.V., Tischenkova I.F., Jelliffe R.W. Population Pharmacokinetic Modeling of Carbamazepine by Using the Iterative Bayesian (IT2B) and the Nonparametric EM (NPEM) Algorithms: Implications for Dosage. J Clin Pharmac and Therapeutics (2001) 26: 213-223.
Reference: PAGE 23 (2014) Abstr 3135 [www.page-meeting.org/?abstract=3135]
Poster: Drug/Disease modeling - CNS