Estimation of Relative Bioavailability of Controlled-Release Carbamazepine Tablets Based on Routine TDM Data
K. Vucicevic(1), B. Miljkovic(1), M. Pokrajac (1), I. Grabnar(2)
(1) Department of Pharmacokinetics, Faculty of Pharmacy, University of Belgrade, Serbia; (2) Faculty of Pharmacy, University of Ljubljana, Slovenia
Objectives: Controlled-release (CR) formulation of carbamazepine (CBZ) tablets, in contrast to immediate-release (IR) form, show lower peak-trough fluctuation of CBZ concentration which leads to less adverse effects, and allow more convenient twice-daily dosing regimen. The aim of the study was to investigate relative bioavailability (FR) of CR relative to IR CBZ tablets.
Methods: In total 379 epileptic outpatients' data were retrospectively collected from routine therapeutic drug monitoring. CBZ was administered 2-4 times per day in the form of 200 mg IR (Karbamazepin; Galenika, Serbia, or Karbapin; Hemofarm, Serbia) or 400 mg CR tablets (Tegretol CR400; Novartis Pharma, Switzerland). Patients were on stable dosage regimen for at least 14 days, either on mono or polytherapy, and 1-2 concentrations per patient were available . PK analysis was performed by a population modeling approach using NONMEM (Version V, level 1.1, GloboMax LLC, USA) and Visual-NM (Version V, R.D.P.P., France) assuming one-compartmental model with first-order absorption and elimination. The FOCE method was used. Based on literature data absorption rate constants were fixed at 0.224 h-1 and 0.077 h-1 for IR and CR formulations, respectively . Validation of the final model was performed.
Results: Model building set included 124 (47 %), while model validation set included 25 (54 %) of patients taking CR CBZ tablets. Interindividual variability of CBZ apparent clearance (CL/F) was best described by exponential error model, while additive error model most adequately characterized residual variability in CBZ concentrations. Inclusion of CBZ formulation significantly improved model (ΔOBJ was decreased by 25.029 compared to base model), and reduced unexplained interindividual variability. In the backward elimination step the influence CBZ formulation on FR was removed (ΔOBJ was 2.171 compared to full model). The interindividual coefficient of variability for CBZ CL/F was 36.5 (31.6-40.7) %, whereas the residual variability was 1.18 (0.98-1.36) mg/mL in the final model. Model validation indicated little bias, good precision and acceptable predictive performance.
Conclusions: In the present study, no difference in bioavailable fraction between CR and IR formulations was observed (FR = 1). The results from the study with sparse data are in compliance with the results in a previously reported data-rich study with well-timed blood samples during the absorption phase.
 Carlsson KC, Hoem NO, Glauser T, et al. Development of a population pharmacokinetic model for carbamazepine based on sparse therapeutic monitoring data from pediatric patients with epilepsy. Clin Ther. 2005;27:618-626.
 USP DI Volume I: Drug Information for the Health Care Professional, 24th ed. Greenwood Village, Co: Thomson Micromedex; 2004:709-716.