Therapeutic Index Estimation of Antiepileptic Drugs: A Systematic Literature Review Approach

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Our study aimed to determine whether data obtained from the medical literature can be used to estimate the therapeutic index of 5 antiepileptic drugs (AEDs): carbamazepine, lamotrigine, phenobarbital, phenytoin, and valproate.


We performed a literature search using PubMed and EMBASE to collect published safety, efficacy, and therapeutic monitoring data for 5 AEDs and extracted all relevant information into a drug- and study-specific drug database. For each AED, we summarized (1) type, severity, and incidence of toxicity-related adverse events and toxicity-associated range of drug doses or concentrations; (2) effective versus toxic concentration and dose (therapeutic range); and (3) therapeutic drug monitoring practices. We defined therapeutic index as the ratio of the minimum toxic concentration to the minimum effective concentration.


We reviewed a total of 810 full-text articles and extracted data from 163. The literature suggests that the therapeutic index of phenytoin is 2. The therapeutic indices of phenobarbital and valproate exceed 2. There were insufficient data to precisely quantify the therapeutic indices of carbamazepine and lamotrigine.


For some drugs, this approach offers a low-cost method of therapeutic index estimation. Our results can serve as preliminary data for future trials and as guidance for US Food and Drug Administration decision making regarding narrow therapeutic index classification.

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