Assessing Bioequivalence of Antiepileptic Drugs: Are the Current Requirements too Permissive?

Abstract

Purpose: In order to evaluate the permissiveness of current bioequivalence requirements for antiepileptic drugs we investigated how accurate Cmax and AUC0-t of generic antiepileptic drugs approved in Brazil are in comparison to reference products. Methods: Data collected from assessment reports of approved bioequivalence studies archived in the Brazilian regulatory agency in 2007-2012 were: geometric mean ratios and 90% confidence intervals (CI) for Cmax and AUC0-t, intra-subject variability (CV) of Cmax and AUC0-t and number of subjects. Results: The average difference in Cmax and AUC0-t between generic and reference products was 5% and 3%, respectively. Maximum deviation from 1.00 of the CI of Cmax can achieve 15-20% (demonstrated in 27% of studies); for AUC0-t, 25% of studies showed the deviation can be >10%. All studies that used adequate number of subjects for a 90% CI of 0.90-1.11 complied with it for AUC0-t, except one of carbamazepine, but only 33% complied with it for both AUC0-t and Cmax. The CV was strongly correlated to the maximum CI deviation for AUC0-t (CV of approximately 15% corresponding to deviation of 10%). Studies that presented maximum CI deviation ≤ 10 % together with CV ≤ 15% for AUC0-t represented 65% of the total. Weaker correlation was observed for Cmax and no correlation was seen between maximum CI deviation and number of subjects. Conclusions: Modification in legislation for bioequivalence of antiepileptic drugs is suggested, not only with constraint of AUC0-t 90% CI to 0.90-1.11, but also with limitation of the CV to 15%, as to assure similar variance in pharmacokinetics and diminish the risk of critical plasma-level fluctuation when switching between generic and reference formulations. Although most generics presented differences ≤ 10% in AUC0-t compared to their references, some narrow therapeutic index drugs displayed differences that could be clinically significant after product substitution. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

Safety of switching from brand-name to generic levetiracetam in patients with epilepsy

“… 7 , 11 , 16 , 17 Consequently, some authors argued that the requirements related to the bioequivalence of AEDs were too permissive, especially for medications with narrow therapeutic indices. 18 Subsequent studies, however, led to an important change in the paradigm regarding the use of generic AEDs. Ting et al 19 confirmed bioequivalence of the brand-name and generic lamotrigine; Privitera et al 5 showed bioequivalence of the several generic formulations of lamotrigine.…”

Possible Genetic Determinants of Response to Phenytoin in a Group of Colombian Patients With Epilepsy

“…The availability of this information for all patients would have allowed an accurate correlation between CYP2C9 genotypes, plasmatic levels of phenytoin and therapeutic response, as well as a more precise attribution of causal relationship in ADRs according to the Naranjo algorithm, which includes supratherapeutic plasma levels of the suspect drug as one of the items to be evaluated. While phenytoin has a narrow therapeutic range, there is evidence to suggest that this drug should not be freely interchangeable (Gidal, 2009;Rediguieri and Zeredo, 2014). Therefore, the lack of control over which specific…”

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

“…One relates to the narrow therapeutic window of some epilepsy medications, and the consequent concern that current requirements to assess bioequivalence may be too permissive for ASMs. 16 The second argument relates to switchability between different generics of the same ASM, that is, as to whether and when two generic products that are found to be bioequivalent to the same reference brand product can be considered bioequivalent to one another. 17,18 The aim of the current article is to address these arguments by reviewing bioequivalence results for generic products of second-generation ASMs approved in Europe through the centralized, mutual recognition or decentralized authorization procedures.…”

“…There are two recurrent arguments that are often raised to question the safety of generic substitution in epilepsy. One relates to the narrow therapeutic window of some epilepsy medications, and the consequent concern that current requirements to assess bioequivalence may be too permissive for ASMs 16 . The second argument relates to switchability between different generics of the same ASM, that is, as to whether and when two generic products that are found to be bioequivalent to the same reference brand product can be considered bioequivalent to one another 17,18 …”