title: Therapeutic Index Estimation of Antiepileptic Drugs: A Systematic Literature Review Approach.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: *Duke Clinical Research Institute, Durham; †Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC; and Office of Generic Drugs, US Food and Drug Administration, Silver Spring, MD.
authors.forename: Rachel G
authors.initials: RG
authors.lastname: Greenberg
authors.forename: Chiara
authors.initials: C
authors.lastname: Melloni
authors.forename: Huali
authors.initials: H
authors.lastname: Wu
authors.forename: Daniel
authors.initials: D
authors.lastname: Gonzalez
authors.forename: Lawrence
authors.initials: L
authors.lastname: Ku
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Hill
authors.forename: Christoph P
authors.initials: CP
authors.lastname: Hornik
authors.forename: Michael
authors.initials: M
authors.lastname: Cohen-Wolkowiez
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Guptill
mesh_terms: D000927:Anticonvulsants / Q000627:therapeutic use*; D016206:Databases, Bibliographic / Q000706:statistics & numerical data; D016903:Drug Monitoring / Q000379:methods*; D004827:Epilepsy / Q000188:drug therapy*; D006801:Humans; D016896:Treatment Outcome
chemical_list: D000927:Anticonvulsants