Population Pharmacokinetics of Carbamazepine and Estimation of Influencing Factors
I. Bondareva, O. Andreeva
The Research Institute of Physical - Chemical Medicine, Moscow, Russia
Objectives: Carbamazepine (CBZ) is an effective anticonvulsant for partial and generalized seizures in both adults and children. Because of a considerable interindividual variability of CBZ PK and PD, many investigators have recommended individualizing CBZ dosage regimens based on TDM for better seizure control. This study aimed at developing PK models for post-induction CBZ behaviour in children, adults and elderly patients as well as at estimating the influence of dosage form on CBZ PK and drug – drug interactions for combined therapy with CBZ plus another “old” AEDs.
Methods: The population PK analysis was performed using the USC*PACK software (the NPEM program) based on a linear one-compartment model and routinely collected CBZ TDM data (peak – trough strategy). The influence of age and dosage form (CBZ versus CBZ-retard) on CBZ PK parameters was examined. After internal and external validation, the estimated population PK models for age subgroups, dosage forms and CBZ duotherapy were used for Bayesian adaptive control in clinical practice.
Results: TDM data of 237 epileptic patients on chronic CBZ monotherapy were used to develop CBZ PK models for adults (n=99), children (n=90) and elderly (n=48) separately. The PK models for CBZ controlled – release dosage form were based on data of 176 epileptic patients on chronic CBZ-retard monotherapy (adults, n=94; children, n=82). Two subpopulations of slow and fast CBZ metabolizers were discovered by the NPEM in adults. CBZ PK drug – drug interactions were estimated from data of 235 patients on chronic CBZ duotherapy (CBZ+VPA, n=75; CBZ+PHN, n=43; CBZ+PHB, n=117). A statistically significant difference in the mean Kel values for the age subgroups (p<0.01) and in the mean Ka estimates for the compared dosage forms (p<0.001) was found. The estimated PK model parameters for CBZ duotherapy were in good agreement with theory of such PK interactions. Great interindividual variability of CBZ serum level to dose ratios was found in all studied populations.
Conclusions: The study demonstrated the need for TDM and individualizing of CBZ dosage regimens. A PK model based only on the population mean values even when adjusted for the known covariates cannot correct well for interindividual variability, but these models can be used to develop an initial dosage regimen as well as to make an individualized patient-specific model from sparse TDM data for Bayesian adaptive control in optimal epilepsy management.