Bioequivalence Between Generic and Branded Lamotrigine in People With Epilepsy: The EQUIGEN Randomized Clinical Trial

Abstract

Importance: Switching between generic antiepileptic drugs is a highly debated issue that affects both clinical care and overall health care costs.

Objective: To evaluate the single-dose pharmacokinetic bioequivalence of 3 (1 branded and 2 generic drugs) on-market, immediate-release lamotrigine drug products.

Design, setting, and participants: The Equivalence Among Antiepileptic Drug Generic and Brand Products in People With Epilepsy (EQUIGEN) single-dose study is a crossover, prospective, sequence-randomized, replicate pharmacokinetic study conducted at 5 US academic epilepsy centers. Fifty adults (≥18 years) with epilepsy who were taking concomitant antiepileptic drugs and not currently receiving lamotrigine were enrolled between July 18, 2013, and January 19, 2015. Every participant was randomly assigned to 1 of 3 equivalent sequences, each comprising 6 study periods, during which they had blood draws before and after medication administration. Forty-nine participants were included in intention-to-treat analyses.

Interventions: Participants received a single 25-mg dose of immediate-release lamotrigine at the start of each period, with the branded and the 2 most disparate generic products each studied twice. Lamotrigine was selected as the antiepileptic drug of interest because of its wide use, publications indicating problems with generic switches, and complaints to the US Food and Drug Administration regarding generic products. Both participants and study personnel were blinded to the specific generic products selected.

Main outcomes and measures: The primary outcome was bioequivalence between products. Maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) were compared, and average bioequivalence (ABE) was established if the 90% CIs of the ratios of the 2 products were within equivalence limits (80%-125%).

Results: Of the 50 randomized participants, 49 (98%) received all 3 lamotrigine products and completed at least 3 pharmacokinetic assessments and 46 (92%) completed all 6 pharmacokinetic assessments. Among the 49 participants, 28 (57%) were men and 21 (43%) were women, 42 (86%) self-identified as white, and 46 (16) years was the mean (SD) age. The 3 drug products were considered bioequivalent because the 90% CIs were within equivalence limits (lowest and highest CI limits for Cmax, 92.6% and 110.4%; for AUC0-96, 96.9% and 101.9%). Replicate testing demonstrated no significant differences in within-subject variability across the 3 products (likelihood ratios, χ22 for log-transformed variables: AUC0-96, 2.58; Cmax, 0.64; and AUC0-∞, 4.05; P ≥ .13) and that the 3 products were also bioequivalent according to scaled ABE and individual bioequivalence criteria with no subject × formulation interaction (Cmax, 0.00; AUC0-96, 0.54; and AUC0-∞, 0.36; P ≥ .76).

Conclusions and relevance: This study provides evidence that the disparate lamotrigine products studied are bioequivalent when tested in people with epilepsy taking concomitant antiepileptic drugs.

Trial registration: clinicaltrials.gov Identifier: NCT01733394.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Berg reported being a site investigator for industry-sponsored research by Upsher-Smith Laboratories, Sunovion, Neuropace, Lundbeck, Pfizer, King Pharmaceuticals, Sage Therapeutics, and Acorda Therapeutics. Dr Welty reported serving as chair of the treatments committee of the American Epilepsy Society and receiving personal fees from Upsher-Smith Laboratories and Eisai. Dr Gidal reported receiving personal fees from UCB Pharma, Upsher-Smith Laboratories, Eisai, and Sunovion. Dr Szaflarski reported being a paid consultant for GW Pharmaceuticals, Upsher-Smith Laboratories, Sage Pharmaceuticals, and Biomedical Systems; serving on the editorial boards of Epilepsy & Behavior, Epilepsy Currents (contributing editor), Journal of Epileptology (associate editor), Journal of Medical Science, Folia Medica Copernicana, Restorative Neurology and Neuroscience (associate editor), and Conference Papers in Medicine; receiving research funding from the US Department of Defense, US FDA, American Epilepsy Society, Sage Pharmaceuticals, Eisai, UCB Pharma, the National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke, the State of Alabama (for Carly’s Law), and the University of Alabama at Birmingham; and being an expert witness in legal proceedings. Dr Dworetzky reported receiving personal fees from Sleep Med and Best Doctors. Dr Pollard reported receiving grants from GlaxoSmithKline, Lundbeck, SK Pharmaceuticals, Upsher-Smith Laboratories, Eisai, and Cognizance Biomarkers; receiving personal fees from Lundbeck; and being part owner of a company executing an NIH Small Business Innovation Research program for biomarker research, which at this time has no financial value. Dr Elder reported owning GlaxoSmithKline stock and receiving personal fees from Mylan and Teva. Drs W. Jiang and X. Jiang reported being current employees of the FDA. Dr Switzer reported being a current employee of SuccinctChoice Medical Communications. Dr Privitera reported receiving grants from UCB Pharma, GW Pharmaceuticals, and Neuren; receiving personal fees from Astellas Pharma, Sage Pharmaceuticals, and Upsher-Smith Laboratories; and serving as an expert witness in legal proceedings. No other disclosures were reported.

Figures

Figure 1.. Participant Disposition Diagram

aThree participants completed only the first 3 pharmacokinetic assessments. AED indicates antiepileptic drug; PKA, pharmacokinetic assessment.

Figure 2.. Mean Lamotrigine Plasma Concentrations After Single-Dose Administration of 1 Branded Lamotrigine and 2 Disparate Generic Lamotrigine Products

Main graph, lamotrigine plasma concentration from 0 to 96 hours. Inset, lamotrigine plasma concentration from 0 to 360 minutes (0-6 hours). gLTG indicates generic lamotrigine; error bars, SD

Figure 3.. Mean Ratio of Drug Formulation Estimates for 3 Lamotrigine Drug Products

The area under the concentration–time curve (AUC0-96) is designated as an orange circle (percentage point estimate [PE]) and orange line (90% CI); Cmax is designated as a blue circle (percentage PE) and blue line (90% CI). Brand indicates branded lamotrigine; FDA, US Food and Drug Administration; and gLTG, generic lamotrigine.