Abstracts

Rationale: The controversy surrounding the bioequivalence and interchangeability between brand and generic of some drug classes such as antiepileptic drugs, some of them known as having narrow therapeutic index (NTI), raised the need to modify and tighten FDA bioequivalence criteria for NTI drugs. Clear and proper identification of NTI drugs is therefore a prerequisite to apply these new bioequivalence criteria. The objective of this work is to evaluate how antiepileptic drugs are classified according to the actual definition and the proposed criteria from FDA to identify NTI drugs.Methods: Literature search was performed to assess whether phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine and levetiracetam fulfill the following features of NTI drugs: 1) little separation between therapeutic and toxic doses, 2) subtherapeutic concentration/small change in dose may lead to therapeutic failure, 3) need for therapeutic drug monitoring (TDM), 4) low-to-moderate within subject variability (≤ 30%), 5) doses are often adjusted in small increments (<20%). A score was calculated for each drug based on the number of criteria that have been met. The scores were then compared between antiepileptic drugs that have been already defined as NTI and those who have not been classified as NTI.Results: Phenytoin, carbamazepine and valproic acid, which are already qualified as NTI drugs in literature, obtained the highest score as they met all the general NTI criteria with the exception of the dose adjustment in small increments criterion (approx. 30 to 50%). Phenobarbital (score=1), lamotrigine (score=2) and levetiracetam (score=0) obtained the lowest score. This scoring system has, however, strong limitations. The general features that may characterize NTI drugs are non-objective and are based on non-specific criteria. A set of clear quantitative criteria describing the relationship between drug concentrations and clinical efficacy or toxicity are much needed. Moreover, this relationship is not well delineated for the majority of antiepileptic drugs.Conclusions: More objective metrics to differentiate between NTI and non-NTI drugs are needed. New metrics that take into account the variability in patients pharmacokinetics, pharmacodynamics are being investigated and compared to the described scoring system.