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

Show simple item record Ekberg, Henrik Mamelok, Richard D. Pearson, Thomas C. Vincenti, Flavio Tedesco-Silva, Helio [UNIFESP] Daloze, Pierre 2016-01-24T13:52:33Z 2016-01-24T13:52:33Z 2009-05-15
dc.identifier.citation Transplantation. Philadelphia: Lippincott Williams & Wilkins, v. 87, n. 9, p. 1360-1366, 2009.
dc.identifier.issn 0041-1337
dc.description.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. en
dc.description.sponsorship F. Hoffmann-La Roche Ltd, Basel, Switzerland.
dc.format.extent 1360-1366
dc.language.iso eng
dc.publisher Lippincott Williams & Wilkins
dc.relation.ispartof Transplantation
dc.rights Acesso restrito
dc.subject Calcinuerin inhibitors en
dc.subject Mycophenolate mofetil en
dc.subject Target drug concentration en
dc.title The Challenge of Achieving Target Drug Concentrations in Clinical Trials: Experience From the Symphony Study en
dc.type Artigo
dc.contributor.institution Lund Univ
dc.contributor.institution Mamelok Consulting
dc.contributor.institution Emory Univ
dc.contributor.institution Univ Calif San Francisco
dc.contributor.institution Universidade Federal de São Paulo (UNIFESP)
dc.contributor.institution CHUM Montreal
dc.description.affiliation Lund Univ, Univ Hosp, Dept Nephrol & Transplantat, S-20502 Malmo, Sweden
dc.description.affiliation Mamelok Consulting, Palo Alto, CA USA
dc.description.affiliation Emory Univ, Sch Med, Dept Surg, Emory Transplant Ctr, Atlanta, GA 30322 USA
dc.description.affiliation Univ Calif San Francisco, Moffitt Hosp, Transplant Serv, San Francisco, CA USA
dc.description.affiliation Universidade Federal de São Paulo, Div Nephrol, Hosp Rim & Hipertensao, São Paulo, Brazil
dc.description.affiliation CHUM Montreal, Notre Dame Hosp, Dept Surg, Quebec City, PQ, Canada
dc.description.affiliationUnifesp Universidade Federal de São Paulo, Div Nephrol, Hosp Rim & Hipertensao, São Paulo, Brazil
dc.identifier.doi 10.1097/TP.0b013e3181a23cb2
dc.description.source Web of Science
dc.identifier.wos WOS:000266048100015


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