Abstracts

Rationale: Therapeutic equivalence between generic and brand name anti-epileptic drugs (AEDs) has been a concern among patients, clinical practitioners and scientists. Many have doubt about the use of single dose, healthy volunteer testing protocol to establish bioequivalence (BE) in abbreviated new drug applications (ANDA) because epilepsy patients are taking AEDs chronically for seizure control. In order to ensure therapeutic equivalence of generic AEDs, Office of Generic Drugs at FDA sponsored several clinical studies to determine BE of a selected AED in epilepsy patients using different dosing protocols. Methods: Lamotrigine (LTG) was selected as the AED to determine its pharmacokinetic (PK) parameters in epilepsy patients and to compare them between different drug products (e.g. generic vs. brand name, and between two generic products with the most disparate PK parameters in ANDA approvals). We sponsored three clinical studies, namely Bioequivalence in Epilepsy Patients (BEEP) study (chronic dose) and Equivalence of Generic and Brand Name Drugs in Epilepsy (EQUIGEN) (chronic and single dose). Qualified subjects were adults with epilepsy, receiving LTG as monotherapy or polytherapy (BEEP and EQUIGEN chronic dose), or not receiving LTG (EQUIGEN single dose). All concomitant medications remained at stable dose throughout the study. Each generic or brand name product was studied twice in randomized sequences to assess within subject variability. Plasma levels of LTG were obtained at the end of each test period to ensure steady state attained and determine the 90% confidence intervals of Cmax-ss and AUCss for each LTG product. Independent of the clinical study, we also performed simulation studies to model population PK parameters as another assessment. Population pharmacokinetic (PK) parameters of high and low generic lamotrigine (HLTG and LLTG) were modeled and compared with Lamictal^®. Results: BEEP study was successfully completed with 35 epilepsy patients. Among them 34 patients completed all 4 treatments. As the primary outcome, the average BE testing was performed. For secondary outcome, the adverse effect and seizure count were analyzed. For EQUIGEN chronic study, all 36 subjects were randomized, 35 of them completed all 4 treatment periods. The PK data will be completed in the coming months. The single dose EQUIGEN study is still ongoing with an estimated completion date towards early 2015. Simulation data suggested that BE is expected/achieved even under the worse-case scenario based on the ANDA LTG submission data. Conclusions: Post-marketing BE studies of AEDs using epilepsy patients can be achieved in an outpatient setting with excellent compliance. The results of BEEP and chronic dose EQUIGEN studies will be presented, and future directions will be discussed.