Sources of lamotrigine pharmacokinetic variability: A systematic review of population pharmacokinetic analyses

Background: Lamotrigine (LTG) is a new generation antiepileptic drug. However, relatively high interindividual pharmacokinetic variability of this drug has been documented. Therefore, several population pharmacokinetic studies of lamotrigine were conducted to identify factors influencing its pharmacokinetics. Objective: This systematic review aimed to summarize significant factors influencing LTG pharmacokinetics and their relationships with pharmacokinetic parameters as well as the magnitude of pharmacokinetic variability. Methods: Four databases i.e. PubMed, Scopus, CINAHL Complete, and Science Direct were systematically searched from their inception to March 2020. Population pharmacokinetic studies of LTG conducted in humans using a nonlinear-mixed effect approach were eligible for a systematic review. Results: Nineteen studies were included in this systematic review. Most studies characterized LTG pharmaco-kinetics as a one-compartment model structure. The three most frequently identified significant covariates influencing LTG clearance included concomitant antiepileptic drugs, body weight, and genetic polymorphisms. Approximately 58% of the studies did not externally validate the models. Conclusions: For clinical application, LTG maintenance dose could be optimized using population pharmacokinetic models employing covariates such as concomitant antiepileptic drugs, body weight, and genetic polymorphisms. However, these models should be assessed for their predictability in the target population before utilizing such models in clinical settings.