Abstracts

Rationale: Based on anecdotal reports, surveys, small retrospective case series, high switchback rates, and database studies there is a physician and patient perception that generic AEDs are not always equivalent to brand products. To study these concerns, pharmacokinetic (PK) trials using subjects who had increased seizures, unexpected adverse effects, or unexpected level changes with generic switches have been proposed. However, concerns have been raised about the feasibility of recruitment of adequate numbers of these so called, "enriched" subjects. Methods: To help determine if the concerns about potential generic inequivalence in people with epilepsy with multiple co-morbidities are valid and to mimic real-life circumstances, the EQUIvalence among GENeric AEDs (EQUIGEN) study group undertook a multi-center, chronic-dose, replicate, 4-period, pharmacokinetic trial comparing 2 generic products of lamotrigine assessed to be the most disparate. Subjects were enrolled at 6 sites. At enrollment, subjects were queried about potential enriched-subject qualifying events associated with any AED brand-to-generic, generic-to-generic, or generic-brand switching within the past 5 years. Medical records of the subjects who reported a potential qualifying event were reviewed. The events were scored using modified Naranjo criteria for seizure exacerbation or adverse events. Subjects were considered to have an enriched subject qualifying event if the modified Naranjo score was at least 7 points. Unexpected level changes were identified if the percentage difference of the AED level (constrained by draw time to trough, mid-dose, or peak) after the switch from one version of the product to another (same mg dose) exceeded two times the coefficient of variation (CV). The CV was based on the individual's past levels, if 3 or more were available, or the CV 75^th percentile population calculated separately for concomitant inhibitors, neutral, and inducer medications, if only 1 or 2 baseline levels were available. Results: Five of the 35 subjects (14%) had qualifying events meeting the enriched-subject criteria. Three had seizure exacerbations and two had increased adverse events. One of the three subjects with seizure exacerbations also had a decrease in AED blood level that exceeded twice the CV_individual. Four of the qualifying events occurred with switches of lamotrigine products and one with a switch of levetiracetam products. Two occurred with brand-to-generic and three occurred with generic-to-generic switches. Conclusions: The number of subjects who agreed to participate in the EQUIGEN chronic-dose trial who met the enriched-subject criteria for a qualifying event associated with generic switching was relatively small, suggesting that it may be difficult to recruit adequate numbers of subjects into enriched subject studies of generic AEDs.