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The challenge of achieving target drug concentrations in clinical trials: experience from the Symphony study.

Ekberg, Henrik LU ; Mamelok, Richard D; Pearson, Thomas C; Vincenti, Flavio; Tedesco-Silva, Hélio and Daloze, Pierre (2009) In Transplantation 87(9). p.1360-1366
Abstract
BACKGROUND: The Symphony study compared four immunosuppressant regimens, defined by protocol-specified target drug concentrations. This subanalysis examines actual drug levels and the implications on the interpretation of results. METHODS: De novo renal transplant patients (n=1645) were randomized to receive mycophenolate mofetil (2 g/day) and corticosteroids in combination with standard-dose cyclosporine A (CsA; 150-300 ng/mL for 3 months then 100-200 ng/mL), or daclizumab induction and low-dose CsA (50-100 ng/mL), low-dose tacrolimus (Tac; 3-7 ng/mL), or low-dose sirolimus (SRL; 4-8 ng/mL). RESULTS: Low-dose Tac was significantly superior for renal function, acute rejection, and graft survival at 12 months. Median trough levels of CsA,... (More)
BACKGROUND: The Symphony study compared four immunosuppressant regimens, defined by protocol-specified target drug concentrations. This subanalysis examines actual drug levels and the implications on the interpretation of results. METHODS: De novo renal transplant patients (n=1645) were randomized to receive mycophenolate mofetil (2 g/day) and corticosteroids in combination with standard-dose cyclosporine A (CsA; 150-300 ng/mL for 3 months then 100-200 ng/mL), or daclizumab induction and low-dose CsA (50-100 ng/mL), low-dose tacrolimus (Tac; 3-7 ng/mL), or low-dose sirolimus (SRL; 4-8 ng/mL). RESULTS: Low-dose Tac was significantly superior for renal function, acute rejection, and graft survival at 12 months. Median trough levels of CsA, Tac, or SRL were toward the high end of target ranges in all groups, and 50% to 60% were within target. During weeks 1 to 8, only 6.5% to 11.0% of patients were consistently within target. At week 8, the range of concentrations encompassing 75% of patients on standard-dose CsA was 141 to 321 ng/mL; for low-dose CsA, 62 to 159 ng/mL; for low-dose Tac, 4.3 to 10.0 ng/mL, and for low-dose SRL, 4.4 to 11.2 ng/mL. The protocol-defined target levels were approximately, but not fully achieved. CONCLUSIONS: To replicate the Symphony study results in clinical practice, the protocol-defined drug concentration targets should be aimed for, but the concentrations actually achieved may be regarded as acceptable. Future clinical studies should include measures of how well target drug levels were achieved to better guide further attempts to develop new regimens designed to reduce or eliminate calcineurin inhibitors. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Transplantation
volume
87
issue
9
pages
1360 - 1366
publisher
Lippincott Williams & Wilkins
external identifiers
  • WOS:000266048100015
  • PMID:19424036
  • Scopus:67649595499
ISSN
1534-6080
DOI
10.1097/TP.0b013e3181a23cb2
language
English
LU publication?
yes
id
89a9720e-9202-4651-aa56-3741e9dc8f7f (old id 1412538)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/19424036?dopt=Abstract
date added to LUP
2009-06-02 09:13:01
date last changed
2017-02-26 04:26:38
@article{89a9720e-9202-4651-aa56-3741e9dc8f7f,
  abstract     = {BACKGROUND: The Symphony study compared four immunosuppressant regimens, defined by protocol-specified target drug concentrations. This subanalysis examines actual drug levels and the implications on the interpretation of results. METHODS: De novo renal transplant patients (n=1645) were randomized to receive mycophenolate mofetil (2 g/day) and corticosteroids in combination with standard-dose cyclosporine A (CsA; 150-300 ng/mL for 3 months then 100-200 ng/mL), or daclizumab induction and low-dose CsA (50-100 ng/mL), low-dose tacrolimus (Tac; 3-7 ng/mL), or low-dose sirolimus (SRL; 4-8 ng/mL). RESULTS: Low-dose Tac was significantly superior for renal function, acute rejection, and graft survival at 12 months. Median trough levels of CsA, Tac, or SRL were toward the high end of target ranges in all groups, and 50% to 60% were within target. During weeks 1 to 8, only 6.5% to 11.0% of patients were consistently within target. At week 8, the range of concentrations encompassing 75% of patients on standard-dose CsA was 141 to 321 ng/mL; for low-dose CsA, 62 to 159 ng/mL; for low-dose Tac, 4.3 to 10.0 ng/mL, and for low-dose SRL, 4.4 to 11.2 ng/mL. The protocol-defined target levels were approximately, but not fully achieved. CONCLUSIONS: To replicate the Symphony study results in clinical practice, the protocol-defined drug concentration targets should be aimed for, but the concentrations actually achieved may be regarded as acceptable. Future clinical studies should include measures of how well target drug levels were achieved to better guide further attempts to develop new regimens designed to reduce or eliminate calcineurin inhibitors.},
  author       = {Ekberg, Henrik and Mamelok, Richard D and Pearson, Thomas C and Vincenti, Flavio and Tedesco-Silva, Hélio and Daloze, Pierre},
  issn         = {1534-6080},
  language     = {eng},
  number       = {9},
  pages        = {1360--1366},
  publisher    = {Lippincott Williams & Wilkins},
  series       = {Transplantation},
  title        = {The challenge of achieving target drug concentrations in clinical trials: experience from the Symphony study.},
  url          = {http://dx.doi.org/10.1097/TP.0b013e3181a23cb2},
  volume       = {87},
  year         = {2009},
}