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Time‐Dependent and Immunosuppressive Drug–Associated Adverse Event Profiles in De Novo Kidney Transplant Recipients Converted from Tacrolimus to Sirolimus Regimens
Author(s) -
Felix Maria Julia Pereira,
Felipe Claudia Rosso,
TedescoSilva Hélio,
Osmar MedinaPestana José
Publication year - 2016
Publication title -
pharmacotherapy: the journal of human pharmacology and drug therapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.227
H-Index - 109
eISSN - 1875-9114
pISSN - 0277-0008
DOI - 10.1002/phar.1692
Subject(s) - medicine , sirolimus , tacrolimus , calcineurin , adverse effect , mycophenolic acid , tolerability , cumulative incidence , regimen , immunosuppression , gastroenterology , transplantation , prednisone , kidney transplantation , urology
Study 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. Design Prospective safety analysis of data from a prospective, randomized, open‐label, controlled study. Patients 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). Measurements and Main Results Both groups were followed for 24 months after transplantation for immunosuppressive regimen–associated and time‐dependent occurrences of adverse events ( AE s) and serious adverse events ( SAE s). Before conversion from TAC to SRL , the cumulative incidence of AE s was 98%; 25% were SAE s. Gastrointestinal AE s (66%) and infections (58%) were the most frequent AE s. The incidences of TAC and MPS dose reductions due to AE s 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 AE s (100% vs 98%) and SAE s (27% vs 30%). The most common AE s 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) AE s 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 AE s occurred in 11.7% of patients receiving SRL and 13.6% of patients receiving TAC . Conclusion SRL / MPS treatment was associated with a time‐dependent higher incidence of gastrointestinal and skin and subcutaneous tissue AE s, 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 AE s.