title: A Systematic Literature Review Approach to Estimate the Therapeutic Index of Selected Immunosuppressant Drugs After Renal Transplantation.
abstract: 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).
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: *Department of Pediatrics, Pennsylvania State University, Hershey, PA;†Duke Clinical Research Institute, Durham, NC;‡Department of Pediatrics, Duke University, Durham, NC; and§Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC.
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Ericson
authors.forename: Kanecia O
authors.initials: KO
authors.lastname: Zimmerman
authors.forename: Daniel
authors.initials: D
authors.lastname: Gonzalez
authors.forename: Chiara
authors.initials: C
authors.lastname: Melloni
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Guptill
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Hill
authors.forename: Huali
authors.initials: H
authors.lastname: Wu
authors.forename: Michael
authors.initials: M
authors.lastname: Cohen-Wolkowiez
mesh_terms: D016572:Cyclosporine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016903:Drug Monitoring / Q000379:methods; D016568:Drugs, Generic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016030:Kidney Transplantation / Q000379:methods*; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016559:Tacrolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D013810:Therapeutic Equivalency; D000076162:Therapeutic Index
chemical_list: D016568:Drugs, Generic; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D020123:Sirolimus; D016559:Tacrolimus