Abstracts

Rationale: Adherence is a fundamental component of any clinical trial. It is crucial when evaluating drug pharmacokinetics (PK), particularly when looking to detect modest differences as in the EQUIGEN bioequivalence study. Here we report the incorporation of a Medication Event Monitoring System (MEMS) cap, that uses  a microchip to record the time and date of each bottle opening, as an adjunct to traditional pill counts and diaries. Methods: This chronic-dose study was a 6-center, prospective, randomized, investigator-blinded, 4-period PK trial of chronic dosing of two generic 100 mg lamotrigine (LTG) products to determine the differences in PK parameters after generic-to-generic switching. Each period lasted 13-15 days during which subjects were required to take the study drug every 12 hours with a 1 hour window. Doses consisted of 1, 2, 3, or 4 tablets. The two products were each administered in two separate periods, providing replicate PK data.Subjects were counseled intensively about the need for strict adherence at each PK visit, and completed a dose diary with every dose. A reminder system consisting of a study coordinator programmed dual alarm clock to assist with adherence that was affixed to the diary notebook. At the start of each period, the subjects received a new bottle of 128 lamotrigine 100 mg tablets with Tablet counts were confirmed by both central pharmacy and site coordinator.  Adherence was assessed using double tablet counts, dose diaries and MEMS data. Adherence criteria required that during each period the subjects miss no more than one dose from period start to the minus 9 day, take the entire daily dose from days minus 8 to minus 4 and take each dose within a one hour window of the dose time from days minus 3 to the PK day.  Results: 35 patients were recruited. Two subjects dropped out prior to completion of period 2 and are not included in this analysis. The mean (±SD) number of days on treatment in a period was 16.4±5.3 in the 33 subjects who completed all 4 periods of this study during 132 completed treatment periods for a total of 4,330 scheduled doses. Eight dosing errors occurred (0.18%) for which the subjects were unaware. In each of these subjects, perfect adherence was reported in the subject dose diaries. Two subjects unknowingly took an extra dose. & 4 unknowingly missed doses. In these subjects, perfect adherence was also self-reported. Two subjects had possible partial dose errors. In each of these instances, the subject insisted that no dose errors occurred despite the data being indicative of the errors. Conclusions: Our data suggest that even in highly motivated, well monitored study patients who were physician selected, dosing errors can still occur. Given the inherent variability of AED PK, even modest lapses in adherence have the potential to skew clinical and PK outcomes in trials. Use of MEMS technology greatly improved detection of modest & partial non-adherence, and we believe, improved quality of PK data. We suggest that future clinical trials of AEDs adopt this strategy. Funding: Funded by contract HHSF223201110112A from the FDA, a grant from the Epilepsy Foundation, and a generous gift from the American Epilepsy Society.