{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T23:11:09Z","timestamp":1789686669009,"version":"4.0.1"},"reference-count":33,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2016,1,22]],"date-time":"2016-01-22T00:00:00Z","timestamp":1453420800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["accpjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pharmacotherapy"],"published-print":{"date-parts":[[2016,2]]},"abstract":"Study Objective<\/jats:title>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.<\/jats:p><\/jats:sec>Design<\/jats:title>Prospective safety analysis of data from a prospective, randomized, open\u2010label, controlled study.<\/jats:p><\/jats:sec>Patients<\/jats:title>A total of 119 adult kidney transplant recipients who received tacrolimus (TAC<\/jats:styled-content>), mycophenolate sodium (MPS<\/jats:styled-content>), and prednisone between February 2008 and May 2010; after 3 months of this regimen, 60 of these patients were randomized to conversion from TAC<\/jats:styled-content> to sirolimus (SRL<\/jats:styled-content>\/MPS<\/jats:styled-content> group), and 59 patients continued with the TAC<\/jats:styled-content> regimen (TAC<\/jats:styled-content>\/MPS<\/jats:styled-content> group).<\/jats:p><\/jats:sec>Measurements and Main Results<\/jats:title>Both groups were followed for 24 months after transplantation for immunosuppressive regimen\u2013associated and time\u2010dependent occurrences of adverse events (AE<\/jats:styled-content>s) and serious adverse events (SAE<\/jats:styled-content>s). Before conversion from TAC<\/jats:styled-content> to SRL<\/jats:styled-content>, the cumulative incidence of AE<\/jats:styled-content>s was 98%; 25% were SAE<\/jats:styled-content>s. Gastrointestinal AE<\/jats:styled-content>s (66%) and infections (58%) were the most frequent AE<\/jats:styled-content>s. The incidences of TAC<\/jats:styled-content> and MPS<\/jats:styled-content> dose reductions due to AE<\/jats:styled-content>s were 1.7% and 12%, respectively. After conversion, no significant differences were noted in the SRL<\/jats:styled-content>\/MPS<\/jats:styled-content> group versus the TAC<\/jats:styled-content>\/MPS<\/jats:styled-content> group in the cumulative incidences of AE<\/jats:styled-content>s (100% vs 98%) and SAE<\/jats:styled-content>s (27% vs 30%). The most common AE<\/jats:styled-content>s were gastrointestinal (70% vs 54%, p=0.23) and infection (77% vs 73%, p=0.79) in the SRL<\/jats:styled-content>\/MPS<\/jats:styled-content> versus TAC<\/jats:styled-content>\/MPS<\/jats:styled-content> 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<\/jats:styled-content>\/MPS<\/jats:styled-content> group compared with the TAC<\/jats:styled-content>\/MPS<\/jats:styled-content> group. Cox proportion regression analysis showed a higher relative risk for gastrointestinal (hazard ratio [HR]<\/jats:styled-content> 1.9, 95% confidence interval [CI<\/jats:styled-content>] 1.2\u20133.01, p<0.05) and skin and subcutaneous tissue (HR<\/jats:styled-content> 2.5, 95% CI<\/jats:styled-content> 1.1\u20134.1, p<0.05) AE<\/jats:styled-content>s in the SRL<\/jats:styled-content>\/MPS<\/jats:styled-content> group compared with the TAC<\/jats:styled-content>\/MPS<\/jats:styled-content> group. AE<\/jats:styled-content>\u2010related dose reductions occurred in 18.3% of patients receiving SRL<\/jats:styled-content> and 3.3% of patients receiving TAC<\/jats:styled-content>. MPS<\/jats:styled-content> dose reductions due to AE<\/jats:styled-content>s occurred in 11.7% of patients receiving SRL<\/jats:styled-content> and 13.6% of patients receiving TAC<\/jats:styled-content>.<\/jats:p><\/jats:sec>Conclusion<\/jats:title>SRL<\/jats:styled-content>\/MPS<\/jats:styled-content> treatment was associated with a time\u2010dependent higher incidence of gastrointestinal and skin and subcutaneous tissue AE<\/jats:styled-content>s, which occurred mainly during the first 6 months after conversion from TAC<\/jats:styled-content>\/MPS<\/jats:styled-content>. Although the treatments with SRL<\/jats:styled-content> or TAC<\/jats:styled-content> after 3 months of transplantation showed different safety profiles, both regimens demonstrated adequate tolerability, with low rates of early discontinuation related to AE<\/jats:styled-content>s.<\/jats:p><\/jats:sec>","DOI":"10.1002\/phar.1692","type":"journal-article","created":{"date-parts":[[2016,1,22]],"date-time":"2016-01-22T09:12:12Z","timestamp":1453453932000},"page":"152-165","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Time\u2010Dependent and Immunosuppressive Drug\u2013Associated Adverse Event Profiles in De Novo Kidney Transplant Recipients Converted from Tacrolimus to Sirolimus Regimens"],"prefix":"10.1002","volume":"36","author":[{"given":"Maria Julia Pereira","family":"Felix","sequence":"first","affiliation":[{"name":"Nephrology Division Hospital do Rim Universidade Federal de S\u00e3o Paulo S\u00e3o Paulo 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