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.
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.
Authors: Barbara M Davit; Patrick E Nwakama; Gary J Buehler; Dale P Conner; Sam H Haidar; Devvrat T Patel; Yongsheng Yang; Lawrence X Yu; Janet Woodcock Journal: Ann Pharmacother Date: 2009-09-23 Impact factor: 3.154
Authors: A G Barbari; M A Masri; A G Stephan; B El Ghoul; S Rizk; N Mourad; G S Kamel; H E Kilani; A S Karam Journal: Exp Clin Transplant Date: 2006-06 Impact factor: 0.945
Authors: J M Morales; J M Campistol; H Kreis; G Mourad; J Eris; F P Schena; J M Grinyo; G Nanni; A Andres; N Castaing; Y Brault; J T Burke Journal: Transplant Proc Date: 2005-03 Impact factor: 1.066
Authors: S Vitko; Z Wlodarczyk; L Kyllönen; Z Czajkowski; R Margreiter; L Backman; F Perner; P Rigotti; B Jaques; D Abramowicz; M Kessler; J Sanchez-Plumed; L Rostaing; R S Rodger; D Donati; Y Vanrenterghem Journal: Am J Transplant Date: 2006-03 Impact factor: 8.086
Authors: C M O'Seaghdha; R McQuillan; A M Moran; P Lavin; A Dorman; P O'Kelly; D M Mohan; P Little; D P Hickey; P J Conlon Journal: Clin Transplant Date: 2009 Aug-Sep Impact factor: 2.863
Authors: Melissa A Wilk; Andrew T Braun; Philip M Farrell; Anita Laxova; Donna M Brown; James M Holt; Camille L Birch; Nadiya Sosonkina; Brandon M Wilk; Elizabeth A Worthey Journal: Cold Spring Harb Mol Case Stud Date: 2020-02-03