Abstracts

Rationale: Equivalence between brand and generic antiepileptic products has been a source of controversy with many questioning the clinical applicability of FDA single dose, normal volunteer testing. We conducted a prospective, randomized, blinded, four period pharmacokinetic (PK) trial of chronic dosing of two generic lamotrigine (LTG) products at 6 centers. Our aim was to determine the magnitude of differences in PK parameters after generic to generic switches using disparate generic products. Methods: Two FDA approved LTG generic products were chosen that showed the most disparity in PK parameters. Maximum concentration and area under the curve data from FDA abbreviated new drug application (ANDA) was combined with in vitro dissolution and content testing to help the selection of two most disparate products. Qualified subjects were adults with epilepsy, receiving LTG in a dose that was a multiple of 100 mg, with equal AM and PM doses, either as monotherapy or polytherapy. Subjects were not receiving valproate, abstained from grapefruit juice and did not drink alcohol for 72 hours before PK testing. All concomitant medications remained at stable dose throughout the study. Two weeks of stable outpatient dosing with rigorous compliance measures via tablet counts, patient diaries, and computerized compliance caps on bottles was followed by two steady state blood levels on days -2 and -1 before PK testing. For dosing days -14 to -9, subjects could only miss a single dose; for days -8 to -4, subjects could not miss any doses; for days -3 to -1, all doses had to be taken within one hour of scheduled time. On day 0 after receiving the AM dose in a fasting state, 19 blood levels were obtained over 12 hours while in a research facility. Each generic product was studied twice in randomized sequences. 90% confidence intervals around the difference between the two generic products for Cmax and AUC were calculated and compared with FDA ANDA criteria. Results: 36 subjects were randomized, so far 28 have completed all 4 treatment periods, with 7 others are expected to complete by July 2014. In a total of 131 completed treatment periods, there were only 11 instances of minor violations of compliance criteria leading to a makeup period, and no dropouts due to lack of compliance. Five subjects were considered "enriched" because they reported unexpected adverse effects or loss of seizure control after a generic switch prior to study entry. No serious adverse events or loss of seizure control was seen after crossover between generic products in any subject. No early PK periods were performed due to unacceptable adverse effects. Approximately ¼ of the subjects were receiving concomitant enzyme inducing antiepileptic drugs. Cmax and AUC data with subgroup analyses will be presented. Conclusions: Chronic dosing of antiepileptic drugs with excellent compliance can be achieved in an outpatient pharmacokinetic study. Bioequivalence data for the two disparate generic products will be presented.