Abstracts

Rationale: Chronic-dose pharmacokinetic studies require a high level of subject medication regimen adherence. Incomplete adherence with dosing regimens is one of the reasons the FDA favors single dose over chronic dose studies for generic bioequivalence testing. Strict adherence criteria were required in the EQUIGEN chronic-dose study, a 6-center, prospective, randomized, investigator-blinded, replicate, 4-period pharmacokinetic (PK) trial of chronic dosing of two, disparate, FDA-approved generic lamotrigine (LTG) products to determine the differences in PK parameters after generic-to-generic switching. In this study we assessed medication regimen adherence in highly compliant subjects. Methods: Adherence to the study drug regimen (dosed every 12 hours) was assessed using double tablet counts, daily dose diaries and Medication Event Monitoring System (MEMS) capped bottles. MEMS caps contain a microchip that records the time and date of each bottle opening. Each 2-week PK period concluded with a 12-hour PK session. Adherence criteria required that during each period the subjects miss no more than one dose from period start to day minus-9, take the entire daily dose from days minus 8 to minus 4 and take each dose within one hour of the dose time from days minus 3 to the PK day. Results: Thirty-five subjects were recruited and 26 have completed all 4 periods with 8 subjects in progress. One dropout occurred in PK period-1 and is not included in the results. In a total of 116 completed treatment periods with 3248 doses, there have been 8 (0.25%) dosing errors for which the subjects were unaware: —— →Two subjects unknowingly took an extra dose: MEMS cap opened twice at a dose time with tablet count at the PK admission in agreement with an extra dose taken. →Four subjects unknowingly missed doses: Diaries had all doses recorded as taken, but in 3 subjects the MEMS cap was not opened at one of the dose times and an extra dose was present in the bottles on tablet count. In the other, the MEMS cap was opened at all dose times, but an extra dose was in the bottle. →Two subjects had possible partial dose errors: One subject was missing 1 tablet from the bottle suggesting an extra tablet was taken with a dose (regimen: 2 tablets per dose). The other had 1 extra tablet in the bottle suggesting that with one dose only 3 tablets were taken (regimen: 4 tablets per dose). —— In each of these instances, the subject insisted that no dose errors occurred despite the data being highly consistent with the errors. There were no clinical correlates. Conclusions: Our data demonstrate that unrecognized dose errors are made, albeit rarely, by highly adherent patients. Thus, in patients with epilepsy, even when perfect adherence is reported, it is possible that transient AEs or a breakthrough seizure is due to a dose error for which the patient is unaware, although there were no clinical effects from the dose errors in our subjects.