A Systematic Literature Review Approach to Estimate the Therapeutic Index of Selected Immunosuppressant Drugs After Renal Transplantation.

Journal Article (Journal Article;Review;Systematic Review)

BACKGROUND: Drugs that exhibit close margins between therapeutic and toxic blood concentrations are considered to have a narrow therapeutic index (NTI). The Food and Drug Administration has proposed that NTI drugs should have more stringent bioequivalence standards for approval of generic formulations. However, many immunosuppressant drugs do not have a well-defined therapeutic index (TI). METHODS: We sought to determine whether safety, efficacy, and pharmacokinetic data obtained from the medical literature through a comprehensive literature search could be used to estimate the TI of cyclosporine, tacrolimus, and sirolimus. In this analysis, we considered TI ≤2 as a criterion to define a drug as having an NTI. RESULTS: Published literature indicates that cyclosporine has a TI of 2-3, which falls just short of our criteria to be classified as having an NTI. We found sirolimus and tacrolimus to have a therapeutic range of 5-12 ng/mL and of 5-20 ng/mL, respectively, but were unable to calculate the TI. CONCLUSIONS: Although the current literature does not provide a clear indication that these drugs have an NTI, the routine use of therapeutic drug monitoring in clinical practice suggests that more stringent testing of their pharmacokinetic and pharmacodynamic properties should be performed before the approval of generic formulations.

Full Text

Duke Authors

Cited Authors

  • Ericson, JE; Zimmerman, KO; Gonzalez, D; Melloni, C; Guptill, JT; Hill, KD; Wu, H; Cohen-Wolkowiez, M

Published Date

  • February 2017

Published In

Volume / Issue

  • 39 / 1

Start / End Page

  • 13 - 20

PubMed ID

  • 28081041

Pubmed Central ID

  • PMC5235278

Electronic International Standard Serial Number (EISSN)

  • 1536-3694

Digital Object Identifier (DOI)

  • 10.1097/FTD.0000000000000364


  • eng

Conference Location

  • United States