Abstracts

Rationale: Lamotrigine is one of the mostly prescribed anti-epileptic drugs (AEDs) due to the availability of generic forms, broad spectrum efficacy, and good tolerability. Lamotrigine is available in immediate-release (IR) and extended-release (ER) formulations. Recent clinical studies funded by the US Food and Drug Administration (FDA) have demonstrated bioequivalence (BE) between brand and generic lamotrigine IR tablet products (Epilepsia, 2015. 56: 1415-24) as well as between two different generic lamotrigine IR tablet products (Lancet Neurol, 2016. 15: 365-72) in patients with epilepsy. Neurologists continue to raise questions regarding modified release (MR) AEDs because of the complexity in the formulation design, quality attribute profile, and in vivo pharmacokinetics (PK). FDA is rigorously evaluating the BE of MR AEDs to assess whether additional data (e.g. within-subject variability of study products) may be needed to support the approval of generic ER products. Methods: Approved generic applications were reviewed to select two generic lamotrigine ER tablet products which are most different from the reference product, Lamictal XR, in terms of modified release mechanism, in vitro dissolution profiles, and in vivo PK under fasting and fed conditions. In vitro dissolution test of selected lamotrigine ER tablets was performed under compendial and novel dissolution conditions using Lamictal XR tablet as the reference. The strength which was approved based on a waiver of in vivo BE study and demonstrated dissolution profiles which are most different from Lamictal XR was selected for BE assessment in healthy subjects . A physiologically based PK (PBPK) model was developed to predict BE outcome of the PK study. Results: Eight generic lamotrigine ER tablet applications have been approved to date. Despite different modified release mechanisms employed by the generic and reference products, they meet quality standards and have demonstrated BE in healthy subjects using the 50 mg strength. Two products were selected for the in vitro dissolution study due to the most difference in in vitro dissolution profiles and in in vivo PK under fed condition based on generic application. The 200 mg strength of one generic product demonstrated the most difference from Lamictal XR with a f2 similarity factor of 32.9 in the novel dissolution media simulating the fed state. Therefore, it was selected for in vivo BE assessment. The BE study was designed as a single center, randomized, single dose, two-sequence, four-period, two-treatment, fully replicated crossover study in 30 subjects under the fed condition, comparing the 200 mg strength between one generic product and Lamictal XR. The PBPK model predicted BE between the selected generic product and Lamictal XR. Conclusions: The outcome of this study will help address public concerns regarding generic switching because it provides data on the within subject variability of both brand and generic MR AED products. Funding: Supported by FDA contract HHSF223201210030I.