Abstracts

Rationale: Bioequivalence (BE) has served as an important criterion in FDA approval of generic drug products. In most cases average BE is used and individual profiles alone are not a basis for BE evaluations. Nevertheless, in addition to average BE outcomes in a recent BE study in Epilepsy Patients (BEEP¹) we considered a sub-population of generic-brittle epilepsy patients to evaluate individual pharmacokinetic (PK) profiles, as well as seizure and non-seizure adverse events. Methods: For each of 34 generic-brittle patients, PK profiles from the BEEP study (two Lamictal and two lamotrigine profiles per patient) were inspected for a >20% difference between brand and generic. For subjects that exhibited such a difference, both seizure and non-seizure adverse events (AEs) were inspected. Additionally, PK profiles were inspected for subjects who exhibited the most seizure and non-seizure AEs. Results: Of 34 subjects, one (Subject 024) exhibited generic AUC values that were >20% different than brand (Fig. 1). For Subject 024, AUC was about 78% compared to brand. Subject 024 showed the second highest number of non-seizure AEs (7 total, which was 12.5% of all AEs), which were transient, not serious, and showed no association in distribution with test or reference product (3R,0T,1R,3T). Four AEs were headache -- three on brand and one on generic. Subject 025 had the most non-seizure AEs (9 total, none serious); the distribution of which was not associated with test or reference product (4R,1T,0R,4T) and not attributed to the slightly greater PK profile of generic-vs-brand (108% for Cmax,107% for AUC). Subject 026 had the most seizures, predominantly on generic (19R,93T,40R,115T). Generic was 95% and 103% of brand for Cmax and AUC, respectively (Fig. 2). For Subject 026, seizure worsening was not attributable to brand-vs-generic PK profile differences. Conclusions: In the BEEP study, one subject exhibited a >20% difference in PK profiles but had similar AE frequency and pattern on generic and brand product. Another subject exhibited the most AEs, which were not attributable to brand or generic, or their slight difference in PK profiles. Another subject had the most seizures, mostly associated with generic study phases, although the generic pharmacokinetic profile was practically the same as that of brand. Characterization of this subject and other factors contributing to the seizure differences warrants further investigation. ¹Polli J, Ting T, Jiang W.Can We Trust Standard Healthy Volunteer Data to Assess Generic Drug Quality: LTG Experience in Patients? 66^th AAN Annual Meeting; 2014 April 29; Philadelphia, PA.