Population pharmacokinetic model of carbamazepine derived from routine therapeutic drug monitoring data

Abstract

The aim of the present study was to develop a population pharmacokinetic model of carbamazepine from routine therapeutic drug monitoring data. Steady-state carbamazepine plasma concentrations determined by homogenous enzyme immunoassay technique, dosing history including cotherapy, schedule of blood sampling, and patients' demographic characteristics were collected retrospectively from patients' chart histories. A one-compartment model was fitted to the data using nonlinear mixed effects modeling. The influence of weight, age, gender, smoking, allergy, carbamazepine daily dose, and cotherapy on clearance (CL/F) was evaluated. Additionally, bioavailability of controlled-release relative to immediate-release tablets was assessed. Two hundred sixty-five patients (423 concentrations) were used to develop a population pharmacokinetic model. The population estimate of CL/F from the base model was 5.14 L/h with interindividual variability of 50.20%. Patients' gender, age, smoking, allergy, cotherapy with lamotrigine and benzodiazepines had no effect on CUE Patient weight (WT), daily carbamazepine dose (DCBZ), daily dose of phenobarbitone (DPB) and valproic acid (VPA), when its daily dose exceeded 750 mg, significantly influenced CL/F and were included in the final model: CL/F [L/h] = 5.35 (DCBZ [mg/da/kg]/15)(0.591) (1 + 0.414 (DPB [mg/day/kg]/2) (WT [kg]/70)(0.564) 1.18(VPA) where VPA is 1 if dose is greater than 750 mg or 0 otherwise. No difference in bioavailability of carbamazepine between controlled and immediate-release tablets was detected. The model predictions in the validation set had no bias and satisfactory precision. The model can be used for estimation of carbamazepine CL/F in individual patients in the postautoinduction phase and for selection of optimum dosing regimen in routine patient care.