Population pharmacokinetics of steady-state carbamazepine in Egyptian epilepsy patients

Abstract

What is known and objective: Individualization of carbamazepine (CBZ) dosage regimen in patients with epilepsy based on based on therapeutic drug monitoring (TDM) followed by estimation of pharmacokinetic (PK) parameters can help in better control of epilepsy. Our objective was to establish a population (POP) PK model of CBZ for Egyptian adult and pediatric patients with epilepsy.

Method: Single steady-state (SS) trough plasma concentrations of CBZ were available for 302 patients with epilepsy (55·6% men and 44·4% women) who were categorized as children (n = 118) and adults (n = 184) with mean age (years) ± SD of 10·6 ± 4·8 and 29·4 ± 9·9, respectively. Carbamazepine was given as an oral suspension (n = 19) or controlled release tablet (n = 283) with average dose of 15·0 ± 7·8 mg/kg per day. A one-compartment model with first-order absorption and elimination for SS conditions (ADVAN2, SS2, TRANS2) was applied using NONMEM 6.2. Separate absorption rate constants were modelled for the two formulations. The mean POP CL, its intersubject variability (ISV), as well as residual error of CBZ concentration were estimated.

Results and discussion: The POP estimate for CL was 3·5 L/h with coefficient of variation value of 2·6%, which was consistent with literature data. The ISV on CL was 44·5%. The POP PK model was validated by bootstrap re-sampling, and the individual estimates were within the 95% CI of the bootstrap results. Different covariates that might affect CBZ CL have been evaluated but the limited number of samples per individual prevented precise covariate analysis.

What is new and conclusion: The POP PK model we have developed for CBZ shows good predictive performance in Egyptian adult and pediatric patients with epilepsy. Another PK study to better define the effect of different covariates would improve on the model for dosage individualization.