A Physiologically Based Pharmacokinetic Model for Optimally Profiling Lamotrigine Disposition and Drug-Drug Interactions

Background and ObjectivesLamotrigine (Lamictal((R))) is a broad-spectrum antiepileptic drug available in both immediate-(IR) and extended-release (XR) formulations. Here, we present a new physiologically based pharmacokinetic (PBPK) model for IR and XR formulations of lamotrigine to predict disposition in adults and children, plus drug-drug interactions (DDIs).MethodsModels for lamotrigine IR and XR formulations were constructed using a Simcyp((R)) Simulator. Concentration-time profiles were simulated for lamotrigine IR single (S-D) and steady-state (SS) doses ranging from 25 to 200mg in adults, as well as 2mg/kg (S-D), and 7.7-9.4mg/kg (SS) in children aged between 4 and 17years. Lamotrigine XR profiles were simulated for S-D and SS doses ranging from 250 to 400mg. DDI prediction with lamotrigine was simulated in adults with enzyme-inducing drugs, rifampin(rifampicin) and ritonavir, as well as the enzyme inhibitor, valproic acid.ResultsThe lamotrigine model predicted adult area-under-the-curve (AUC) and peak plasma concentration (C-max) results for IR S-D within 35% of observed data; lamotrigine IR SS dosing was within 10% and 30% of observed data, respectively. Pediatric lamotrigine IR S-D AUC and C-max values were within 10% and 15% of observed data, respectively. AUC and C-max values for lamotrigine XR S-D simulated in adults were within 20% of observed data; similarly lamotrigine XR SS parameters were within 10%. Concerning DDI simulation in adults, predicted-to-observed lamotrigine AUC ratios [AUC(DDI)/AUC(alone)] were within 15% for ritonavir and rifampin, and 20% for valproic acid.ConclusionsOur developed PBPK lamotrigine profile accurately predicts DDIs and lamotrigine IR/XR formulation disposition in adults and children. This PBPK model will be helpful in designing future DDI studies for co-administration of lamotrigine with other drugs and in designing individualized patient dosing regimens.