Abstracts

Rationale: Lamotrigine is a narrow therapeutic index drug for the treatment of epilepsy. Narrow therapeutic index drugs are often implicated in having variable patient response when switching manufacturer. Available lots of Lamotrigine tablets from various manufacturers were analyzed for Content, Impurities, Content Uniformity, and Dissolution. Results were screened by rank order to determine the most disparate generics based on in vitro testing. The identified products were selected for clinical investigation in the Equivalence Among Antiepileptic Drug Generic and Brand Products in People with Epilepsy (EQUIGEN) clinical study.Methods: Samples of 25 mg and 100 mg products were analyzed for Content, Impurities, Content Uniformity, and Dissolution in accordance with the USP monograph. Multiple lots of 100 mg products from manufacturer G2 and G5 were tested. Results for each analysis were rank ordered and the difference between the rank of each result was calculated. The sum of the differences from all analyses for each product was obtained to determine the products with the greatest overall difference in in vitro performance. One lot of brand product (Lamictal , GSK) was also included for reference. Other factors that were considered for final selection of products to be used in the clinical evaluation were formulation composition and available bioequivalence data from ANDA submissions.Results: Content (C) results appear to show typical manufacturer-to-manufacturer variability. Impurities were extremely low or not detected in all lots; thus, not considered in the rankings. Content Uniformity results were evaluated by looking at both the average content (CU) and the acceptance values (AV). Dissolution was rank ordered at each timepoint, but no significant changes were noted; thus the 30 minute ranking (D30) was used for comparison. A wide variation in the early dissolution timepoints was noted; however, clinical relevance of this was not believed to be significant based on the ANDA bioequivalence data. 100 mg products G4 and G5E were selected for a chronic dose study. 25 mg products from manufacturers of G6 and G5 were selected for a single-dose study. Product G7 was initially under consideration instead of G5 ; however, this product was discontinued by the manufacturer after testing was completed. Blinding of results is being maintained to protect the integrity of the clinical evaluation. Conclusions: A method for selecting most disparate generics for a clinical investigation was developed based the sum of differences in rank order for results of in vitro testing. This approach combined with assessment of formulation composition and ANDA bioequivalence data were used to select products for use in the EQUIGEN clinical studies.