title: Including information on the therapeutic window in bioequivalence acceptance.
abstract: OBJECTIVE
  A novel bioequivalence limit is proposed taking into account the therapeutic window.
  
  
  METHODS
  The therapeutic range is introduced as the ratios maximum tolerated dose/therapeutic dose (MTD/D) and the therapeutic dose/lowest effective dose. The performance of the new acceptance range was compared with the methods of Schuirmann and Karalis. The method was retrospectively applied to data of three drugs with a narrow therapeutic window (phenytoin, theophylline and digoxin).
  
  
  RESULTS
  Simulations and examples show that the resulting bioequivalence limits are (1) narrow for narrow-index drugs, (2) expanded for highly variable drugs with a wide therapeutic window and (3) similar to the classical limits for less variable drugs with a wide therapeutic range.
  
  
  CONCLUSIONS
  The approach has the desirable property of resulting in a more narrow acceptance range for doses near the boundaries of the therapeutic window and a wider acceptance range for products with a broad therapeutic window.
authors.affiliation: Interuniversity Institute for Biostatistics and Statistical Bioinformatics, Universiteit Hasselt, and Katholieke Universiteit Leuven, Belgium, Agoralaan 1, B3590 Diepenbeek, Belgium. tom.jacobs@uhasselt.be
authors.forename: Tom
authors.initials: T
authors.lastname: Jacobs
authors.forename: Filip
authors.initials: F
authors.lastname: De Ridder
authors.forename: Sarah
authors.initials: S
authors.lastname: Rusch
authors.forename: Achiel
authors.initials: A
authors.lastname: Van Peer
authors.forename: Geert
authors.initials: G
authors.lastname: Molenberghs
authors.forename: Luc
authors.initials: L
authors.lastname: Bijnens
mesh_terms: D004077:Digoxin / Q000493:pharmacokinetics; D006801:Humans; D020714:Maximum Tolerated Dose; D010672:Phenytoin / Q000493:pharmacokinetics; D013806:Theophylline / Q000493:pharmacokinetics; D013810:Therapeutic Equivalency
chemical_list: D010672:Phenytoin; D004077:Digoxin; D013806:Theophylline