Purpose: Lamotrigine (LTG, Lamictal®) is a broad-spectrum AED available in both immediate-(IR) and extended-release (XR) formulations. PK simulation can be very helpful in visualizing plasma-concentration profiles in different scenarios (e.g., missed doses [Chen, Ther Drug Monit 2013]). Herein, we present a new physiologically based pharmacokinetic (PBPK) model considering UGT enzyme kinetics and an Advanced Dissolution, Absorption and Metabolism (ADAM) model for XR formulation. The objective was to predict LTG disposition within adults; and evaluate the predictive performance of the model through drug-drug interactions (DDIs).
Methods: PBPK models for LTG IR and XR formulations were constructed using Simcyp Simulator (Version 16). Simcyp’s ADAM model was used to predict for XR. Observed PK and model parameters (Clint, VD, ka) were obtained from literature. Concentration-time profiles were simulated for IR single-dose (SD) and steady-state (SS) doses ranging from 25 mg to 200 mg in adults, as well at 2 mg/kg for SD and 8 mg/kg for SS in children between 4 and 17 years of age. Similarly, profiles were also simulated for XR SD and SS doses of 300 mg and 400 mg, respectively. Co-administration of LTG with several drugs was simulated in adults for DDI prediction including enzyme-inducing drugs rifampin and ritonavir, as well as the enzyme-inhibitor valproic acid (VPA). Observed plasma concentration data for LTG was obtained from twenty-eight clinical studies.
Results: The LTG PBPK model predicted concentration-time profiles for IR and XR formulations within 95th and 5th percentiles for both adults and pediatrics. Adult AUC and Cmax results for IR SD were within 30% and 40% of observed data, respectively; IR SS dosing was within 25% and 15% of observed data, respectively. Pediatric patient IR SD AUC and Cmax values were within 45% and 20% of observed data, respectively. The ADAM model included a controlled-release profile for XR where simulated profiles were in good agreement with observed data. AUC and Cmax values for XR SD and SS were within 25% of observed data. The predicted to observed LTG AUC ratio [AUC DDI/AUCalone] was 10% for ritonavir, 30% for rifampin, and 25% for VPA.
Conclusion: Our developed LTG profile using PBPK modeling accurately predicts the concentration-time disposition of LTG for XR and IR formulation profiles in adult and pediatric patients as well as DDI effects.