title: Time-Dependent and Immunosuppressive Drug-Associated Adverse Event Profiles in De Novo Kidney Transplant Recipients Converted from Tacrolimus to Sirolimus Regimens.
abstract: OBJECTIVE
  To evaluate the safety and tolerability of immunosuppressive drugs used in a planned randomized conversion from a calcineurin inhibitor, tacrolimus, to a mammalian target of rapamycin inhibitor, sirolimus, in de novo kidney transplant recipients.
  
  
  METHODS
  Prospective safety analysis of data from a prospective, randomized, open-label, controlled study.
  
  
  METHODS
  A total of 119 adult kidney transplant recipients who received tacrolimus (TAC), mycophenolate sodium (MPS), and prednisone between February 2008 and May 2010; after 3 months of this regimen, 60 of these patients were randomized to conversion from TAC to sirolimus (SRL/MPS group), and 59 patients continued with the TAC regimen (TAC/MPS group).
  
  
  RESULTS
  Both groups were followed for 24 months after transplantation for immunosuppressive regimen-associated and time-dependent occurrences of adverse events (AEs) and serious adverse events (SAEs). Before conversion from TAC to SRL, the cumulative incidence of AEs was 98%; 25% were SAEs. Gastrointestinal AEs (66%) and infections (58%) were the most frequent AEs. The incidences of TAC and MPS dose reductions due to AEs were 1.7% and 12%, respectively. After conversion, no significant differences were noted in the SRL/MPS group versus the TAC/MPS group in the cumulative incidences of AEs (100% vs. 98%) and SAEs (27% vs. 30%). The most common AEs were gastrointestinal (70% vs. 54%, p=0.23) and infection (77% vs. 73%, p=0.79) in the SRL/MPS versus TAC/MPS groups. The incidence of aphthous ulcer (28% vs. 0%, p=< 0.01), sinusitis (10% vs. 0%, p=0.01), dermatitis (15% vs. 3%, p=0.03), and dyslipidemia (35% vs. 14%, p=0.02) were higher in the SRL/MPS group compared with the TAC/MPS group. Cox proportion regression analysis showed a higher relative risk for gastrointestinal (hazard ratio [HR] 1.9, 95% confidence interval [CI] 1.2-3.01, p<0.05) and skin and subcutaneous tissue (HR 2.5, 95% CI 1.1-4.1, p<0.05) AEs in the SRL/MPS group compared with the TAC/MPS group. AE-related dose reductions occurred in 18.3% of patients receiving SRL and 3.3% of patients receiving TAC. MPS dose reductions due to AEs occurred in 11.7% of patients receiving SRL and 13.6% of patients receiving TAC.
  
  
  CONCLUSIONS
  SRL/MPS treatment was associated with a time-dependent higher incidence of gastrointestinal and skin and subcutaneous tissue AEs, which occurred mainly during the first 6 months after conversion from TAC/MPS. Although the treatments with SRL or TAC after 3 months of transplantation showed different safety profiles, both regimens demonstrated adequate tolerability, with low rates of early discontinuation related to AEs.
authors.affiliation: Nephrology Division, Hospital do Rim, Universidade Federal de São Paulo, São Paulo, Brazil.
authors.forename: Maria Julia Pereira
authors.initials: MJ
authors.lastname: Felix
authors.affiliation: Nephrology Division, Hospital do Rim, Universidade Federal de São Paulo, São Paulo, Brazil.
authors.forename: Claudia Rosso
authors.initials: CR
authors.lastname: Felipe
authors.affiliation: Nephrology Division, Hospital do Rim, Universidade Federal de São Paulo, São Paulo, Brazil.
authors.forename: Hélio
authors.initials: H
authors.lastname: Tedesco-Silva
authors.affiliation: Nephrology Division, Hospital do Rim, Universidade Federal de São Paulo, São Paulo, Brazil.
authors.forename: José
authors.initials: J
authors.lastname: Osmar Medina-Pestana
mesh_terms: D000328:Adult; D001938:Brazil / Q000453:epidemiology; D065095:Calcineurin Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D003875:Drug Eruptions / Q000453:epidemiology* / Q000276:immunology / Q000503:physiopathology; D016903:Drug Monitoring; D004359:Drug Therapy, Combination / Q000009:adverse effects; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced* / Q000453:epidemiology / Q000276:immunology / Q000503:physiopathology; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000627:therapeutic use; D015994:Incidence; D007676:Kidney Failure, Chronic / Q000276:immunology / Q000378:metabolism / Q000601:surgery; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000009:adverse effects / Q000627:therapeutic use; D011241:Prednisone / Q000009:adverse effects / Q000627:therapeutic use; D012720:Severity of Illness Index; D020123:Sirolimus / Q000009:adverse effects* / Q000627:therapeutic use; D040521:Subcutaneous Tissue / Q000187:drug effects* / Q000276:immunology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016559:Tacrolimus / Q000009:adverse effects / Q000627:therapeutic use
chemical_list: D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D009173:Mycophenolic Acid; D011241:Prednisone; D020123:Sirolimus; D016559:Tacrolimus
keywords: adverse event; conversion; safety; sirolimus; tacrolimus