Including information on the therapeutic window in bioequivalence acceptance.
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.
Jacobs
Tom
T
Interuniversity Institute for Biostatistics and Statistical Bioinformatics, Universiteit Hasselt, and Katholieke Universiteit Leuven, Belgium, Agoralaan 1, B3590 Diepenbeek, Belgium. tom.jacobs@uhasselt.be
De Ridder
Filip
F
Rusch
Sarah
S
Van Peer
Achiel
A
Molenberghs
Geert
G
Bijnens
Luc
L
D004077:Digoxin / Q000493:pharmacokinetics; D006801:Humans; D020714:Maximum Tolerated Dose; D010672:Phenytoin / Q000493:pharmacokinetics; D013806:Theophylline / Q000493:pharmacokinetics; D013810:Therapeutic Equivalency
D010672:Phenytoin; D004077:Digoxin; D013806:Theophylline