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 C_max and AUC_0-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 C_max and AUC_0-t, intra-subject variability (CV) of C_max and AUC_0-t and number of subjects. Results: The average difference in C_max and AUC_0-t between generic and reference products was 5% and 3%, respectively. Maximum deviation from 1.00 of the CI of C_max can achieve 15-20% (demonstrated in 27% of studies); for AUC_0-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 AUC_0-t, except one of carbamazepine, but only 33% complied with it for both AUC_0-t and C_max. The CV was strongly correlated to the maximum CI deviation for AUC_0-t (CV of approximately 15% corresponding to deviation of 10%). Studies that presented maximum CI deviation ≤ 10 % together with CV ≤ 15% for AUC_0-t represented 65% of the total. Weaker correlation was observed for C_max 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 AUC_0-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 AUC_0-t compared to their references, some narrow therapeutic index drugs displayed differences that could be clinically significant after product substitution. 

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