Abstracts

Rationale: Lamictal XR (lamotrigine ER tablets at strengths of 25, 50, 100, 200, 250, 300 mg) is a second generation anti-epilepsy drug (AED) indicated for the treatment of seizure control. Lamotrigine ER tablets are taken once daily with or without food as per the drug label. As of June 2016, Food & Drug Administration (FDA) has approved eight generic copies of lamotrigine ER tablets which employ different release mechanisms from the reference listed drug (RLD) product owing to the brand-name formulation's patent protection. To demonstrate bioequivalence between generic lamotrigine ER tablets to the RLD, generic applicants are recommended to conduct single-dose, two-way, crossover bioequivalence studies in healthy volunteers comparing the test products at 50 and 200 mg strengths with those of RLD, and other strengths may be eligible for an in vivo bioequivalence study waiver. This study aims to evaluate the brand-to-generic bioequivalence under both fasting and fed conditions using a PBPK absorption model, and to confirm the minimal risk of generic substitution for all strengths approved. Results: The PBPK absorption model was established based on in vitro dissolution profiles submitted in the ADNAs for fasting conditions and dissolution profiles using the new method for fed conditions. The model adequately predicted the observed PK profiles of a single-dose 50-mg lamotrigine ER tablets in humans under fasting and fed conditions (Figures 1 and 2). An IVIVR between in vitro dissolution profiles and deconvoluted in vivo drug release was also successfully established (insets of Figures 1 and 2). Based on the modeling and simulation results, the test/reference ratio with 90% confidence intervals of predicted PK metrics (i.e. Cmax and AUCt) for the generic lamotrigine ER tablets were entirely within the bioequivalence acceptance limits (i.e. 80%-125%) across all strengths under fasting and fed conditions. Conclusions: Based on the single-dose PK simulations, generic lamotrigine ER tablets with a different release mechanism from the reference drug product conform to the bioequivalence requirements of PK metrics (i.e. Cmax and AUCt) at strengths at which a biowaiver was granted. In the current study, virtual clinical trials based on PBPK modeling and simulation are shown to be a powerful tool to assess the potential food effect and to confirm a minimal substitution risk of the generic drug products across all strengths. Funding: FDA