A systematic literature review approach to estimate the therapeutic index of selected immunosuppressant drugs after renal transplantation

Jessica E. Ericson, Kanecia O. Zimmerman, Daniel Gonzalez, Chiara Melloni, Jeffrey T. Guptill, Kevin D. Hill, Huali Wu, Michael Cohen-Wolkowiez

Research output: Contribution to journalReview article

  • 1 Citations

Abstract

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.

LanguageEnglish (US)
Pages13-20
Number of pages8
JournalTherapeutic Drug Monitoring
Volume39
Issue number1
DOIs
StatePublished - Jan 1 2017

Fingerprint

Immunosuppressive Agents
Kidney Transplantation
Pharmaceutical Preparations
Therapeutics
Tacrolimus
Sirolimus
Cyclosporine
Pharmacokinetics
Therapeutic Equivalency
Drug Monitoring
Poisons
United States Food and Drug Administration
Safety

Keywords

  • Cyclosporine
  • Generic
  • Sirolimus
  • Tacrolimus

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

A systematic literature review approach to estimate the therapeutic index of selected immunosuppressant drugs after renal transplantation. / Ericson, Jessica E.; Zimmerman, Kanecia O.; Gonzalez, Daniel; Melloni, Chiara; Guptill, Jeffrey T.; Hill, Kevin D.; Wu, Huali; Cohen-Wolkowiez, Michael.

In: Therapeutic Drug Monitoring, Vol. 39, No. 1, 01.01.2017, p. 13-20.

Research output: Contribution to journalReview article

Ericson, Jessica E. ; Zimmerman, Kanecia O. ; Gonzalez, Daniel ; Melloni, Chiara ; Guptill, Jeffrey T. ; Hill, Kevin D. ; Wu, Huali ; Cohen-Wolkowiez, Michael. / A systematic literature review approach to estimate the therapeutic index of selected immunosuppressant drugs after renal transplantation. In: Therapeutic Drug Monitoring. 2017 ; Vol. 39, No. 1. pp. 13-20
@article{6c0c04520be14a05855aa2e38e87a4ba,
title = "A systematic literature review approach to estimate the therapeutic index of selected immunosuppressant drugs after renal transplantation",
abstract = "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.",
keywords = "Cyclosporine, Generic, Sirolimus, Tacrolimus",
author = "Ericson, {Jessica E.} and Zimmerman, {Kanecia O.} and Daniel Gonzalez and Chiara Melloni and Guptill, {Jeffrey T.} and Hill, {Kevin D.} and Huali Wu and Michael Cohen-Wolkowiez",
year = "2017",
month = "1",
day = "1",
doi = "10.1097/FTD.0000000000000364",
language = "English (US)",
volume = "39",
pages = "13--20",
journal = "Therapeutic Drug Monitoring",
issn = "0163-4356",
publisher = "Lippincott Williams and Wilkins",
number = "1",

}

TY - JOUR

T1 - A systematic literature review approach to estimate the therapeutic index of selected immunosuppressant drugs after renal transplantation

AU - Ericson,Jessica E.

AU - Zimmerman,Kanecia O.

AU - Gonzalez,Daniel

AU - Melloni,Chiara

AU - Guptill,Jeffrey T.

AU - Hill,Kevin D.

AU - Wu,Huali

AU - Cohen-Wolkowiez,Michael

PY - 2017/1/1

Y1 - 2017/1/1

N2 - 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.

AB - 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.

KW - Cyclosporine

KW - Generic

KW - Sirolimus

KW - Tacrolimus

UR - http://www.scopus.com/inward/record.url?scp=85010422720&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85010422720&partnerID=8YFLogxK

U2 - 10.1097/FTD.0000000000000364

DO - 10.1097/FTD.0000000000000364

M3 - Review article

VL - 39

SP - 13

EP - 20

JO - Therapeutic Drug Monitoring

T2 - Therapeutic Drug Monitoring

JF - Therapeutic Drug Monitoring

SN - 0163-4356

IS - 1

ER -