Switchability of Gabapentin Formulations: A Randomized Trial to Assess Bioequivalence Between Neurontin and Gabasandoz on the Individual Subject Level

Abstract

Generic substitution of antiepileptic drugs is generally not advised by neurologists. The present study investigated the switchability of gabapentin 800 mg tablets (Neurontin and Gabasandoz) using an individual bioequivalence (IBE) study design with two batches of each product and assessed whether between‐batch and between‐formulation variability in exposure play a significant role in the within‐subject variability. The trial was analyzed according to the US Food and Drug Administration (FDA) framework to establish IBE. The IBE was shown between both products with the 95% upper confidence bound of the IBE criterion being −2.01 and −2.31 for area under the concentration‐time curve from zero to infinity (AUC0–inf) and peak plasma concentration (Cmax), respectively. Subject‐by‐formulation variability (1.35%) was negligible compared with the within‐subject variability of AUC0–inf with Neurontin (19.0%) and Gabasandoz (23.6%). Inclusion of an additional batch did not significantly change this within‐subject variability (20.2% and 23.6%, respectively). This study shows that substitution of gabapentin 800 mg tablets of Neurontin and Gabasandoz should be possible without affecting clinical outcomes.

Bioequivalence and switchability of generic antiseizure medications (ASMs): A re‐appraisal based on analysis of generic ASM products approved in Europe

“…In a comparative study of bioequivalence data for 65 immediate‐release formulations of various drugs, %CV for AUC has been found to decrease from 30% to 65% when oral bioavailability was <5% to <20% when bioavailability was <80% 58 . The %CV values of gabapentin generics in our analysis were similar to those reported in previous studies 59,60 . In a study that evaluated two gabapentin generics by using a four‐way cross‐over design, %CV for AUC ranged between 14.9% and 23.6% when each generic was compared with the brand, and between 14.6% and 23.3% when the two generics were compared with each other 60 .…”

“…58 The %CV values of gabapentin generics in our analysis were similar to those reported in previous studies. 59,60 In a study that evaluated two gabapentin generics by using a four-way cross-over design, %CV for AUC ranged between 14.9% and 23.6% when each generic was compared with the brand, and between 14.6% and 23.3% when the two generics were compared with each other. 60 These findings are important because they demonstrated that no "drift" occurred when one generic was exchanged for another.…”

Interchangeability among carbamazepine formulations: the impact over epilepsy patients

“…Some studies describe the occurrence of adverse events, clinical deterioration and pharmacokinetic alterations after the substitution from a reference antiepileptic drug for a generic one (Desmarias, Beauclair, Margolese, 2011;Hensler et al, 2013;Lancker et al, 2019;Prasaja et al 2019;Euen, Fadda, 2019). Conversely, literature regarding exchanges between different generic options is scarce (Krauss et al, 2011).…”

“…Few Brazilian studies evaluate the switching among such formulations and its consequences, and yet do not show significant clinical differences (Guilhoto et al, 2009;Trinka, Kramer, Graf, 2011;Lang et al, 2018;Lancker et al, 2019). Thus, it is pivotal to evaluate the effects of interchangeability in clinical practice, mainly in case of patients relying on the Brazilian National Health System.…”

Why Were More Than 200 Subjects Required to Demonstrate the Bioequivalence of a New Formulation of Levothyroxine with an Old One?

“…In order to resolve these issues for the old and new Levothyrox ® formulations, a new replicated bioequivalence trial, based on ad hoc analysis could be conducted. A first option would be to tentatively analyze the trial according to IBE rather than ABE concepts, as recently undertaken for gabapentin [14]. Like levothyroxine, gabapentin is a critical drug in terms of bioequivalence.…”