Equivalence Among Antiepileptic Drug Generic and Brand Products in People With Epilepsy: Single-Dose 6-Period Replicate Design (EQUIGEN Single-Dose Study)

The study proposed in this protocol will determine if bioequivalence testing performed for the FDA translates into similar bioequivalence in a population of people with epilepsy when switching among different generics of the anti-epileptic drug (AED). Based on a variety of pharmacokinetic (PK) data and clinical reports of concern, the example anti epilepsy drug (AED) used for this study will be lamotrigine (LTG).

In this single dose study, people with epilepsy taking AEDs, but not currently taking the test medication, lamotrigine, will be studied. We will use an order-randomized three-sequence six-period replicate design with the two most disparate generics studied in two replicate periods each and the brand (reference) product studied in two additional periods. A standard single dose of the test drug (lamotrigine 25mg) will be administered under controlled conditions (fasting with subsequent standardized meals) with a 12-hour in-facility blood sample collection followed by a collection every 24 hours for a total of a 96 hour sample collection that will be used to establish the pharmacokinetic measures of Cmax, AUC96 and AUC∞. Each period will be separated by at least a 12 day washout interval.

The replicate studies will be used to determine the intra-individual variability of the pharmacokinetic responses of the brand and the two generic products, as well as subject-by-formulation interaction variances. The data will also be used to calculate simultaneously all parameters that are needed to compare the 3 products in average and individual bioequivalence and outlier analyses. The differences between the disparate generics will be used to establish if the current standards translate to equivalence within the limits of the brand intra-subject variation.

The factors we will use to determine the most disparate generics include the results from the in vivo data from the ABE studies submitted to the FDA in the ANDA and in vitro chemical assay (potency) and dissolution data performed on several currently available lots. The intent is to study the specific lot of the generic product predicted to result in the lowest levels and compare it to the specific lot from another generic product predicted to result in the highest levels. Similarly, if multiple lots of the brand products are available, we will perform in vitro testing to establish the most desirable lot to study.

Factors that alter metabolism, including concomitant AEDs that may have hepatic enzyme induction effects will be tracked but not excluded, as long as the dose remains constant, as the goal is to reproduce the 'real life' situation as closely as possible within the practical limits of funding and study size. Subjects receiving valproate as concomitant medication will be excluded because the prolongation of half life would not allow LTG to reliably be completely cleared by 13 days. The criteria that establish an enriched population will also be tracked and used in a secondary analysis, but will not be used as an inclusion requirement. The enriched population is defined as people who experienced an otherwise unexplained increase in seizures or adverse effects, or a substantial change in AED level after a switch in AED products.

The discovery of any subject-by-formulation interaction outliers (i.e. subjects with differential pharmacokinetic reactions to a pair of formulations) will raise considerable concerns about equivalence. Recently established methods in the statistical analysis of outliers in crossover studies will be used to determine if any outliers are present.

Qualified subjects will be screened and upon fulfilling inclusion/exclusion criteria and signing the informed consent will be enrolled in the study and enter the randomization phase (2-30 days). Subjects will be randomized according to a sealed allocation list that will be balanced for sequence and provided to each site prior to the first subject enrollment. Subjects that withdraw prior to completing the third period will be replaced in a randomized manner. The randomization list will be generated by the study statistical group. There are six test periods in three sequences for a sequence-randomized study. During two test periods subjects will receive a single dose of the brand AED and during the other four test periods subjects will receive a single dose from one of the two investigated generics (each twice). The single doses will be administered in the fasting state during an in-facility 12-hour pharmacokinetic session to collect samples to determine Cmax and AUCs. Four additional samples will be drawn at 24, 48, 72, and 96 hours after the dose as an outpatient (making each pharmacokinetic test last for 4 days). Each in-facility pharmacokinetic testing will be separated by a 12-23 day washout period; consistent washout periods of 14 days will be preferred. A final follow-up phone evaluation will be conducted 12-16 days (target 14 days) after the last dose. During the study the subjects will continue their usual concomitant medications, including AEDs, without change.

Investigators will compare the AED levels as measured by Cmax and AUC in each group using average bioequivalence (ABE) and individual bioequivalence (IBE) criteria. Average bioequivalence will be established if the 90% confidence intervals of the geometric mean of Cmax and AUCs for the most disparate generic products compared to each other are entirely within the 80%-125% range (the FDA criteria for bioequivalence) using the two one-sided standard analyses. Otherwise the products will be considered to not be bioequivalent. Similarly, the products will be considered to not be bioequivalent if the criteria for IBE for each generic product compared to the brand product are not met.

Study Population: Approximately 54 subjects (45 subjects to completion).

Number of centers: 3 sites enrolling approximately 18 subjects each.

Duration of study: Approximately 1 year.