(M1530-04-23) Deciphering Sub-Therapeutic Risks: Integrating In Vitro Release and Modeling for Lamotrigine Extended-Release Tablets

Purpose: Lamictal XR (lamotrigine) Extended-Release Tablet (ERT) is indicated for primary generalized tonic-clonic seizures and partial-onset seizures. Its modified-release eroding core is coated with a clear enteric coat with an aperture drilled through on both faces of the tablet (DiffCORE). The DiffCORE enables drug release in the gastric phase, rendering release profiles independent of fasting or fed conditions [1]. However, generic Lamotrigine ERTs submitted to the FDA often lack an aperture design, resulting in no in vitro lamotrigine release in acidic conditions for some formulations, which could lead to a prolonged Tlag under fed conditions. During the transition from Lamictal XR to generic Lamotrigine ERTs under fed conditions or the transition from fasting to fed conditions with generic Lamotrigine ERTs, a prolonged Tlag may result in sub-therapeutic lamotrigine levels, leading to potential breakthrough seizures. The purpose of this research is to explore the quantitative relationship between in vitro lamotrigine release and potential sub-therapeutic lamotrigine levels using physiologically-based pharmacokinetic (PBPK) modeling and non-parametric superposition simulation.

Methods: A fed PBPK model for Lamotrigine ERT was developed based on dissolution and fed study pharmacokinetic (PK) data from ANDA submissions. A wide range of in vitro lamotrigine release profiles with different slopes up to 24 hours in acidic conditions along with dissolution profiles using the same Weibull rate and shape parameters at pH 6.8 were simulated. Simulated dissolution data were incorporated into the PBPK model to simulate individual PK profiles for both reference (Lamictal XR) and generic products in a two-way crossover study design. Bioequivalence (BE) analyses on the simulated two-way crossover studies investigated the impact of in vitro lamotrigine release in acidic conditions on BE conclusions and Tlag. non-parametric superposition was then employed on the aforementioned simulated PK data to simulate the steady state and transition period for each PK profile and assess the relationship between in vitro lamotrigine release in acidic conditions and lamotrigine levels during the transition.

Results: Our results revealed a quantitative correlation between the absence of in vitro lamotrigine release in acidic conditions and prolonged Tlag in simulated in vivo PK data under fed conditions, resulting in lower minimum lamotrigine concentrations during the aforementioned transitions. Additionally, slower, but detectable, in vitro release of lamotrigine from the generic formulation in acidic conditions, as compared to that from the reference product, was correlated with comparable Tlag between the two formulations but with a lower minimum lamotrigine concentration during the aforementioned transition, indicating that the lack of a Tlag difference is not always predictive of lower minimum lamotrigine concentrations during the aforementioned transitions.

Conclusion: Our research has established a model-integrated evidence approach using PBPK modeling with in vitro lamotrigine release in acidic conditions and pH 6.8 as inputs along with population PK modeling to assess the potential for sub-therapeutic lamotrigine levels (i.e., lower minimum lamotrigine concentrations) during the aforementioned transitions. This may be a valuable predictive approach that streamlines generic Lamotrigine ERT development and regulatory assessment.

References: [1] RLD labeling; https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/022115s029lbl.pdf

Acknowledgements: Disclaimer - This abstract reflects the views of the authors and should not be construed to represent FDA’s views or policies.