Abstract
Objective
Lamotrigine is a commonly prescribed anti-epileptic drug. FDA-funded clinical studies demonstrated bioequivalence (BE) for generic lamotrigine immediate-release (IR) products in epilepsy patients with generic substitution. To address the potential concerns about risk of generic-brand substitution of lamotrigine extended-release (ER) products, considering the complexity of controlled release systems and pharmacokinetic variations associated with possible within-subject variability (WSV), this prospective study assessed i) BE of generic and brand lamotrigine ER products in a fully replicated BE study design in healthy subjects and ii) whether such fully replicated study design and WSV data can better support approval of generic lamotrigine ER products.
Methods
This open-label, single-dose, 2-treatment, 4-period, 2-sequence, fully replicated crossover BE study compared generic lamotrigine ER tablet to brand Lamictal XR (200 mg) in 30 healthy subjects under fed condition. Pharmacokinetic (PK) profiles were generated based on intensive blood sampling up to 144 hours.
Results
The two products showed comparable Cmax, AUC0-t and AUC0-inf, while median Tmax values differed, i.e., 10 h for generic and 22 h for brand products, respectively. WSVs for PK metrics were small (~8% of Cmax and ~6% of AUC) and similar between these two products. PK simulation predicted equivalent PK measurements of both products at steady state and after brand-to-generic switch, except the first day upon switching. No serious adverse events were reported.
Significance
The generic lamotrigine ER tablet product demonstrates BE to the brand product in fully replicated BE study design with healthy subjects, supporting the adequacy of two-way crossover study design to demonstrate BE and generic-brand substitution of lamotrigine ER products.
OCT