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CNS Drugs

, Volume 28, Issue 1, pp 69–77 | Cite as

Generic Products of Antiepileptic Drugs: A Perspective on Bioequivalence, Bioavailability, and Formulation Switches Using Monte Carlo Simulations

  • Vangelis Karalis
  • Panos Macheras
  • Meir Bialer
Original Research Article

Abstract

Introduction

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.

Objective

The aim of this study was to provide enlightenment on issues of bioequivalence (BE) and interchangeability of AED products.

Methods

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.

Results

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.

Discussion

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.

Conclusions

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.

Keywords

Drug Product Reference Product Geometric Mean Ratio Generic Drug Product Breakthrough Seizure 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

The authors confirm that they have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

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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Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  1. 1.Laboratory of Biopharmaceutics & Pharmacokinetics, Faculty of PharmacyNational & Kapodistrian University of AthensAthensGreece
  2. 2.Institute of Drug Research, School of Pharmacy and David R. Bloom Center for Pharmacy, Faculty of MedicineThe Hebrew University of JerusalemJerusalemIsrael

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