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PKP-011 Pharmacokinetics of everolimus in combination with mycophenolate sodium and clinical outcomes in renal transplant recipients previously treated with calcineurin inhibitors
  1. NI Oliveira,
  2. CR Felipe,
  3. PGC Hannun,
  4. H Tedesco-Siva,
  5. JO Medina Pestana
  1. Hospital do Rim, Nephrology, São Paulo, Brazil

Abstract

Background Despite advances in immunosuppressive treatment, long-term renal transplantation outcomes have not improved significantly over the last decade. The nephrotoxicity of calcineurin inhibitors (CNIs) is still associated with chronic allograft loss. Therefore, alternative CNI-free immunosuppressive regimens have been tested recently.

Purpose To prospectively evaluate 24 renal transplant patients who were stable under an immunosuppressive regimen consisting of ciclosporin (CSA), corticosteroids and mycophenolate but who were in need of a CNI-free drug regimen due to signs and symptoms of CNI-induced toxicity, per clinical judgment.

Materials and methods Patients were converted from CSA to everolimus (EVR) treatment in association with mycophenolate sodium (720 mg/ day BID) and prednisone. A complete PK study for everolimus was performed 30 days after conversion and patients were followed for 5 years.

Results The mean age of this population was 41.6 ± 8.61 years, 62.5% male and 66.7% Caucasian ethnicity. Mean transplantation time at conversion was 60.8 ± 33.7 months and mean serum creatinine was 1.8 ± 0.5 mg/dL. The initial EVR dose was 2.0 mg/day for the first 7 patients and 4.0 mg/day for 17 patients. After 30 days, the following pharmacokinetic dose-adjusted parameters were calculated: C0 = 2.7 ± 1.2 ng/mL/mg, Cmax 12.0 ± 3.5 ng/mL/mg, Cmin 2.53 ± 1.2 ng/mL/mg, Tmax = 0.8 ± 0.3 h and AUC(0–12) = 59.2 ± 23.2 μg*h/L/mg. Over 5 years of follow-up, this regimen resulted in a number of adverse events: (81.4% infections, 7% cardiovascular and 11.6% gastrointestinal disorders). 25% of the patients discontinued EVR (33% proteinuria, 33% infection, 17% anaemia and 17% dyslipidaemia). After 5 years of follow-up, patients who had a higher 30-day AUC (above 83.8 μg*h/L) and mean trough blood concentration (above 9 ng/mL) during the follow-up period showed a higher incidence of everolimus-associated adverse reactions (mainly dyslipidaemia and hypertriglyceridemia) and higher rates of EVR discontinuation (66.7%). Two patients (8.3%) experienced late biopsy-proven acute rejection. The mean serum creatinine after 5 years of conversion was 2.17 ± 1.02 mg/dL. Patient, graft and death-censored graft survival rates were 96%, 79% and 83%, respectively and EVR discontinuation-free survival was 74%.

Conclusions In a selected kidney transplant population conversion from CSA to EVR was associated with stable renal function over 5 years of follow up. The adverse event profile and the discontinuation rate were associated with higher EVR exposure 30 days after conversion.

No conflict of interest.

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