Application of Physiologically Based Pharmacokinetic Modeling of Lamotrigine Using PK-Sim in Predicting the Impact of Drug Interactions and Dosage Adjustment

Objectives: To build a lamotrigine (LTG) physiologically based pharmacokinetic (PBPK) model (LTG PBPK) and compare it to the clinical data from South Asian Indian patients and use this model to understand the drug interactions of LTG and explore the optimal doses.

Methods and Material: The PBPK model was developed using the PK-Sim software platform and qualified with LTG plasma concentration data from an Indian study. The European population database was chosen as the patient setting in the software. Physiochemical data of LTG and enzyme kinetic data were incorporated from the literature. Dosing protocols were as per the previous study. Interaction models for drug interactions with carbamazepine and valproate were also simulated.

Results: Most of the model predicted concentration-time profiles of LTG at steady-state were well within the observed concentrations. The developed models were suitably qualified. The drug interaction model was used to assess the impact of induction and inhibition of the pharmacokinetic profile of LTG.

Conclusions: The predicted plasma concentrations of the developed PBPK models using the European population database were very similar to the data from Indian patients. The developed LTG PBPK models are applicable in predicting the impact of drug interactions and can yield appropriate LTG doses to be administered.