A Systematic Review of Population Pharmacokinetics of Carbamazepine

Abstract

Janthima Methaneethorn, Manupat Lohitnavy, Nattawut Leelakanok.

Carbamazepine is a narrow therapeutic index drug requiring therapeutic drug monitoring, while population pharmacokinetics is an approach that can aid individualized dosing regimens and to date, several population pharmacokinetic studies of carbamazepine have been conducted. This systematic review aims to summarize the factors influencing carbamazepine pharmacokinetics and model methodologies, and to identify any knowledge gaps, which may then be used to inform future studies. PubMed and Scopus databases were systematically searched from the date of their inceptions to August 2019. All population pharmacokinetic studies of carbamazepine performed in humans using a nonlinear mixed-effect modeling approach were extracted from these databases and included in this review. Twenty-three articles were included. A one-compartment pharmacokinetic model was employed in most of these studies. While body size, carbamazepine dose, co-medications, age, gender, race, and CYP1A2 polymorphism were identified as significant predictors of carbamazepine clearance, weight was the only significant predictor of the volume of carbamazepine distribution. Exponential and additive relationships were the most frequently used models when analyzing respectively inter-individual and residual variability, and the magnitude of inter-individual variability on carbamazepine clearance ranged from 1.5% to 44.5%. Seventeen of the studies contained a model evaluation, and of these, an external evaluation was conducted in ten. This review highlights the significant predictors of carbamazepine pharmacokinetics that have been identified. However, since information regarding the relationship between carbamazepine pharmacokinetic variability and its pharmacodynamics is lacking, future research relevant to this issue may be required.