Factors influencing carbamazepine pharmacokinetics in children and adults: population pharmacokinetic analysis

Objective: The aim of the present study was to build population pharmacokinetic models for the clearance of carbamazepine (CBZ) in two separate populations of Serbian patients with epilepsy, children and adults. Methods: Analysis was performed using 114 and 53 steady-state concentrations of CBZ collected from 98 children and 53 adult epileptic patients, respectively. Mean values of total body weight and age were 31 +/- 13 kg and 8 +/- 3 years in the population of children, and 67 +/- 13 kg and 32 +/- 15 years in the population of adults. The one-compartment model with first order elimination and without absorption was used from the PREDPP (Prediction for Observation Population Pharmacokinetics) library of NONMEM software. Results: The derived final models of CBZ clearance were similar in the target populations. The most important factors which affected typical mean value of CBZ clearance in both populations studied were age of the patients and total daily dose; the CBZ clearance linearly followed increase of these factors. However, the influence of the patients' age was almost 3.4 times higher in the pediatric population than that in adults while the influence of total daily dose of CBZ is similar. On the other hand, final model in the adult population revealed also influence of concomitant therapy with phenobarbital (PB). The magnitude of this effect was +1.61 1 h(-1). The pharmacokinetic models obtained were validated in groups of 18 children and 13 adults with epilepsy. Conclusions: The derived models describe well CBZ clearance in terms of Serbian pediatric and adult epileptic patient characteristics, offering a basis for rational individualization of CBZ dosage regimens.