Abstracts

Rationale: The therapeutic equivalence of FDA approved generics has been questioned by neurologists and patients with epilepsy (www.AESNET.org; Liow, 2007). Aspects contributing towards reported problems of generic antiepileptic drugs (AEDs) may include 1)a nocebo effect with product switching; 2)lack of multiple dose testing in patients, 3)wide BE acceptance criteria, and 4) patient variability. The most common approach to evaluate bioequivalence (BE) is a two-treatment crossover pharmacokinetic (PK) study design in healthy adults. BE is rarely assessed in patients under clinical conditions. Hence, a study design to assess BE in patients with epilepsy was needed, with little guidance available from prior BE practices. Lamotrigine (LTG), viewed by a consensus of epileptologists to have potential BE problems, was selected as study drug. Our goal was to design a BE study to assess whether a commonly used FDA approved generic is bioequivalent to the brand name LTG product in epilepsy patients under clinical use conditions.Methods: The study design considered typical elements of a conventional BE study in healthy adults, such as sample size and analytical capabilities to quantify drug in plasma. The approach also considered the unique aspect of performing a phase 4 BE study in patients already taking LTG for epilepsy. Considered elements included type of cross-over design, type of patients, product dose, steady-state assessment, need for blinding, drug interactions, and subject adherence. Feedback from the Food and Drug Administration, the National Institutes of Health, and the Epilepsy Foundation were incorporated.Results: A study design has been denoted approvable from local and FDA IRBs. It is a double-blind, multiple-dose, full replicate design, PK study of LTG 100mg tablets in enriched patients with epilepsy. The 100mg dose was selected due to most common usage. Inclusion criteria require subjects to be enriched in terms of potential sensitivity to switching. Rather than unblinded or double-dummy, over-encapsulation was selected as the method for blinding. Figure 1 shows in vitro dissolution profiles of over-encapsulated and unblinded products, indicating lack of product adulteration. White colored capsules will be used for over-encapsulation, as patients surveyed most preferred this color. Subjects will each receive the brand name and generic product twice, allowing for three switches between products. Each arm will be about two weeks in duration to allow for steady-state to be achieved (assessed through drug trough determinations). Given LTG s significant drug interactions, study design excludes non-AEDs that may impact LTG PK. The design also includes patient education for dosing compliance.Conclusions: A study design has been proposed to evaluate the BE of generic and brand name LTG tablets in patients with epilepsy. Given the lack of available study designs to assess BE in patients under clinical use conditions, this design can serve as a prototype for assessment of brand and generic equivalence.