title: A randomized long-term trial of tacrolimus and sirolimus versus tacrolimus and mycophenolate mofetil versus cyclosporine (NEORAL) and sirolimus in renal transplantation. I. Drug interactions and rejection at one year.
abstract: BACKGROUND
  To reduce long-term nephrotoxic calcineurin inhibitor dosage, adjunctive sirolimus or mycophenolate mofetil (MMF) was used in a 150-patient, randomized, three-armed trial in cadaveric or human leukocyte antigen non-identical living-donor first renal transplant recipients (n=50/group).
  
  
  METHODS
  Group A received tacrolimus and sirolimus. Target tacrolimus trough levels postoperatively were 10, 8, and 6 ng/mL at 1 month, 6 months, and 1 year, respectively. Group B received tacrolimus and MMF. Target tacrolimus trough levels were 10 and 8 ng/mL at 1 month and 1 year, with a targeted dose of MMF of 1 g twice daily. Group C received cyclosporine A (CsA) (Neoral, Novartis, Basel, Switzerland) and sirolimus with target CsA trough levels of 225 and 175 ng/mL at 1 month and 1 year. Maintenance sirolimus target trough levels were 8 ng/mL in groups A and C. Each group received daclizumab induction and methylprednisolone maintenance. This first of two companion 1-year reports details demographics, drug-dosing interactions, and rejection.
  
  
  RESULTS
  There were no notable differences in group demographics, but a somewhat less favorable course occurred in group C, despite higher bioavailability of sirolimus in group C versus group A (P<0.001). Acute rejection rates were lower in groups A (4%) and B (4%) combined versus group C (14%) (P=0.03). Histopathologic findings were supported by comparing perioperative with 1-year postoperative protocol biopsies.
  
  
  CONCLUSIONS
  This 1-year interim analysis indicates that a decreasing dosage of tacrolimus with either adjunctive sirolimus or MMF may optimize future graft survival versus a less favorable outcome using a similar algorithm with CsA and sirolimus.
authors.affiliation: Department of Surgery, Division of Transplantation, University of Miami School of Medicine, Miami, Florida 33101, USA. gciancio@med.miami.edu
authors.forename: Gaetano
authors.initials: G
authors.lastname: Ciancio
authors.forename: George W
authors.initials: GW
authors.lastname: Burke
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Gaynor
authors.forename: Adela
authors.initials: A
authors.lastname: Mattiazzi
authors.forename: David
authors.initials: D
authors.lastname: Roth
authors.forename: Warren
authors.initials: W
authors.lastname: Kupin
authors.forename: Maud
authors.initials: M
authors.lastname: Nicolas
authors.forename: Phillip
authors.initials: P
authors.lastname: Ruiz
authors.forename: Anne
authors.initials: A
authors.lastname: Rosen
authors.forename: Joshua
authors.initials: J
authors.lastname: Miller
mesh_terms: D000328:Adult; D019540:Area Under Curve; D001682:Biological Availability; D002102:Cadaver; D016572:Cyclosporine / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D006084:Graft Rejection / Q000453:epidemiology* / Q000517:prevention & control; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016030:Kidney Transplantation / Q000276:immunology*; D019520:Living Donors; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D020123:Sirolimus / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016559:Tacrolimus / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013997:Time Factors; D014019:Tissue Donors
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine; D009173:Mycophenolic Acid; D020123:Sirolimus; D016559:Tacrolimus