The Challenge of Achieving Target Drug Concentrations in Clinical Trials: Experience From the Symphony Study

The Challenge of Achieving Target Drug Concentrations in Clinical Trials: Experience From the Symphony Study

Author Ekberg, Henrik Google Scholar
Mamelok, Richard D. Google Scholar
Pearson, Thomas C. Google Scholar
Vincenti, Flavio Google Scholar
Tedesco-Silva, Helio Autor UNIFESP Google Scholar
Daloze, Pierre Google Scholar
Institution Lund Univ
Mamelok Consulting
Emory Univ
Univ Calif San Francisco
Universidade Federal de São Paulo (UNIFESP)
CHUM Montreal
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-de fined 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.
Keywords Calcinuerin inhibitors
Mycophenolate mofetil
Target drug concentration
Language English
Sponsor F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Date 2009-05-15
Published in Transplantation. Philadelphia: Lippincott Williams & Wilkins, v. 87, n. 9, p. 1360-1366, 2009.
ISSN 0041-1337 (Sherpa/Romeo, impact factor)
Publisher Lippincott Williams & Wilkins
Extent 1360-1366
Access rights Closed access
Type Article
Web of Science ID WOS:000266048100015

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