Generic Products of Antiepileptic Drugs: A Perspective on Bioequivalence, Bioavailability, and Formulation Switches Using Monte Carlo Simulations
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Generic products of antiepileptic drugs (AEDs) are currently a controversial topic as neurologists and patients are reluctant to switch from brand products to generics and to switch between generics.
The aim of this study was to provide enlightenment on issues of bioequivalence (BE) and interchangeability of AED products.
Monte Carlo simulations of the classic 2 × 2 BE studies were performed to study the effect of sample size, within-subject variability, and the true difference in pharmacokinetic values of the products under comparison on BE acceptance of generic AED products. Simulations were extended to study the comparative performance of two generic AED products against the same innovative product. The simulated results are compared with literature data on AEDs.
The question with regard to bioavailability (BA) is whether two formulations are different, while for BE the question is whether two formulations are sufficiently similar in terms of extent and rate of absorption. Therefore, the criteria for BA and BE and the statistical analysis involved in their analysis are different. Two generic formulations that meet regulatory approval requirements for generics by being bioequivalent to the same innovative AED may not be bioequivalent to one another and therefore should not be regarded as equal or as therapeutically equivalent products. A switch from a standard or an immediate-release formulation to a modified-release product, which comprises extended-release or delayed-release formulations, should not be regarded as a switch between generics, but rather as a switch between different formulation types.
Switches between bioequivalent generic AED products could potentially lead to larger changes in plasma levels and exposure than the brand-to-generic switch. The simulation work verified the clinical findings that not all generic AED products bioequivalent to the same innovative product are bioequivalent to one another.
Two generic formulations that meet regulatory approval requirements for generics, by being bioequivalent to the innovative AED, may not be bioequivalent to one another. Additional BE criteria are needed for a formulation switch, particularly in epilepsy, where a breakthrough seizure may change a patient’s status from seizure-free to refractory.
KeywordsDrug Product Reference Product Geometric Mean Ratio Generic Drug Product Breakthrough Seizure
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Conflict of interest
The study was not supported by any funding. Dr. Meir Bialer has received in the last 3 years speakers or consultancy fees from Bial, CTS Chemicals, Desitin, Janssen-Cilag, Rekah, UCB Pharma and Upsher-Smith and has been involved in the design and development of new antiepileptics and CNS drugs as well as new formulations of existing drugs. None of the other authors have any conflict of interest to disclose.
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