I. Bondareva, K. Bondareva
The Research Institute of Physical - Chemical Medicine, Moscow, Russia
Objectives: CBZ has been established as an effective anticonvulsant for partial and generalized seizures. The literature results for CBZ are consistent with self-induction of microsomal enzymes, but only few studies with small sample size have reported the pharmacokinetic (PK) characteristics of CBZ autoinduction. Although the PK changes are well documented in general, their magnitude varies among studies. The objective of the study is to identify parameters of a nonlinear PK model for time course of CBZ autoinduction from TDM data.
Methods: TDM data were collected in the Laboratory of Pharmacokinetics of Moscow Medical University. CBZ levels were measured by high performance liquid chromatography. The assay error pattern was used as: SD=0.1+0.1C (where SD is standard deviation of the assay at measured CBZ concentration C). The PK analysis was performed using the USC*PACK based on a one-compartment model with linear absorption. In this nonlinear model, the metabolic rate of elimination asymptotically increases from a preinduction value (D) during time-lag (Lamda) to a maximum value (D+A) after autoinduction. The model was fitted by the NPEM to TDM data of 19 outpatients closely monitored (6 – 13 peak-trough observations per patient) from 1-2 day up to 1.5 – 2 months of started CBZ-monotherapy.
Results: The postinduction CBZ half-lives were estimated as 3.2 – 50.6h (median = 10h) using a one-compartment linear model and TDM data of 99 adult epileptic patients on chronic CBZ-monotherapy [1]. The preinduction CBZ T1/2 values ranged from 26-63h after 200mg CBZ as a single dose in 16 adult healthy volunteers [1]. The mean elimination parameters of the non-linear autoinduction model (D = 0.02 and D+A=0.06 1/h) are in good agreement with the metabolic rate constants in the pre- (0.018 1/h, CV=22.5%) and postinduction (0.07, CV=97.2%) studies. In 19 patients, the mean ratio of post- to preinduction metabolic rate was 2.2 (CV=40%).
Conclusions: The modeling results indicate that CBZ markedly induces its own metabolism. CBZ autoinduction was completed within the first 1 – 3 weeks of monotherapy. The study demonstrated wide interindividual PK variability in CBZ autoinduction and the need for TDM.
References:
[1] Bondareva I., Sokolov A., Tischenkova I., Jelliffe R. Population Pharmacokinetic Modeling of Carbamazepine by Using the Iterative Bayesian and the Nonparametric EM Algorithms: Implications for Dosage. J Clin Pharmac and Therapeutics 2001; 26: 213-223.
Reference: PAGE 22 (2013) Abstr 2724 [www.page-meeting.org/?abstract=2724]
Poster: CNS