Novel bioequivalence approach for narrow therapeutic index drugs

Clin Pharmacol Ther. 2015 Mar;97(3):286-91. doi: 10.1002/cpt.28. Epub 2014 Dec 15.


Narrow therapeutic index drugs are defined as those drugs where small differences in dose or blood concentration may lead to serious therapeutic failures and/or adverse drug reactions that are life-threatening or result in persistent or significant disability or incapacity. The US Food and Drug Administration proposes that the bioequivalence of narrow therapeutic index drugs be determined using a scaling approach with a four-way, fully replicated, crossover design study in healthy subjects that permits the simultaneous equivalence comparison of the mean and within-subject variability of the test and reference products. The proposed bioequivalence limits for narrow therapeutic index drugs of 90.00%-111.11% would be scaled based on the within-subject variability of the reference product. The proposed study design and data analysis should provide greater assurance of therapeutic equivalence of narrow therapeutic index drug products.

MeSH terms

  • Humans
  • Prescription Drugs / pharmacokinetics*
  • Prescription Drugs / standards*
  • Research Design / standards*
  • Statistics as Topic / standards*
  • Therapeutic Equivalency
  • United States
  • United States Food and Drug Administration


  • Prescription Drugs