Abstracts

Rationale: Based on anecdotal reports, small retrospective case series, high switchback rates, and database studies, there is a physician and patient perception that generic antiepileptic drugs (AEDs) are not always equivalent to brand products in treatment of epilepsy. To help determine if the concerns about potential generic inequivalence are valid and to mimic real-life circumstances, the EQUIGEN study group conducted a study of single doses of the brand Lamictal® and two disparate generic products of lamotrigine in people with epilepsy not currently taking lamotrigine.Methods: We undertook a prospective, multi-center (5 sites), masked, replicate, sequence-randomized, 3-sequence, 6-period, single-dose, pharmacokinetic (PK) trial in people with epilepsy on concomitant AEDs. After an extensive review, lamotrigine was selected as the study drug based on its PK profile and available study population. Selection of the 2 most disparate generic products was based on maximum concentration (Cmax) and area under the curve (AUC) data from the FDA abbreviated new drug applications (ANDAs) combined with in vitro dissolution and content testing of commercially purchased products. Generic tablets from 15 separate lots were assessed: 25 mg tablets from 6 manufacturers and 100 mg tablets from 5 manufacturers (one with 4 lots and one with 2 lots). Power analysis determined that 45 subjects would give a 90% probability of rejecting the null hypothesis of non-bioequivalence. Subjects with epilepsy, with or without co-morbidities (excluding comorbidities judged to potentially affect drug absorption), and on ≥1 AED, including hepatic enzyme inducers but not inhibitors (e.g., valproate) nor lamotrigine, were eligible. To minimize confounds, subjects taking sertraline and estrogens were excluded. A 25 mg tablet of lamotrigine was administered in a masked fashion to each subject in a fasting condition at the start of each 96-hour PK period; subsequent periods were separated by a 12-23 day washout period. All concomitant medications remained at stable doses throughout the study. The measured concentration/time values were used to determine the Cmax and AUC, which were used to assess average bioequivalence (ABE), scaled average bioequivalence, and individual bioequivalence (IBE).Results: Of the 59 subjects enrolled, 50 subjects were randomized; 9 screen failures occurred during the baseline phase. Study retention was high with 46 subjects (92%) completing all 6 PK periods. One subject dropped out prior to the third PK period and 3 subjects dropped out after the third but prior to the sixth PK period. No study-related serious adverse events occurred. ABE, scaled ABE and IBE results with special attention to subjects with outlier data will be presented.Conclusions: In conjunction with the EQUIGEN chronic-dose study, the EQUIGEN single-dose study will inform physicians and the public about differences in variability of disparate generic AED lamotrigine products compared to the brand product as used in the real-life situation of treating people with epilepsy on concomitant AEDs with a spectrum of co-morbidities.