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.
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.
Ciancio
Gaetano
G
Department of Surgery, Division of Transplantation, University of Miami School of Medicine, Miami, Florida 33101, USA. gciancio@med.miami.edu
Burke
George W
GW
Gaynor
Jeffrey J
JJ
Mattiazzi
Adela
A
Roth
David
D
Kupin
Warren
W
Nicolas
Maud
M
Ruiz
Phillip
P
Rosen
Anne
A
Miller
Joshua
J
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
D007166:Immunosuppressive Agents; D016572:Cyclosporine; D009173:Mycophenolic Acid; D020123:Sirolimus; D016559:Tacrolimus