Elsevier

Transplantation Proceedings

Volume 42, Issue 8, October 2010, Pages 3050-3052
Transplantation Proceedings

Immunosuppression
Comparative Analysis of Adverse Events Requiring Suspension of mTOR Inhibitors: Everolimus versus Sirolimus

https://doi.org/10.1016/j.transproceed.2010.07.083Get rights and content

Abstract

Background

Inhibitors of mammalian target of rapamycin (mTORi) have been suggested as an alternative to calcineurin inhibitors (CNIs) to treat stable renal transplant recipients. However, their use has been significantly limited owing to a high incidence of side effects.

Objective

To compare the rate of dropout (mTORi elimination and CNI reintroduction) caused by side effects among renal transplant patients converted to everolimus (EVL) or sirolimus (SRL).

Methods

Between October 1999 and February 2010, 409 subjects were converted to an mTORi at least 3 months after transplantation, including 220 (53.8%) to EVL and 189 (46.2%) to SRL. Most patients were under CNI therapy. Patients were followed for a median of 35 months (interquartile range [IQR], 18–50 months).

Results

mTORi treatment was prematurely eliminated due to adverse events in 112 patients. The median time between the initiation of mTORi and discontinuation was 5.7 months (IQR, 1.9–15.7 months; range, 0.2–48 months): 5.5 (IQR, 1.6–16.3) in the EVL group and 7.4 (IQR, 2.6–15.6) in the SRL group. In the EVL group, the drug was stopped in 69 patients (31.4%), and in the SRL group in 43 patients (22.8%; P = .051). The most important causes of discontinuation were severe infections (2.3% in EVL group and 4.8% in SRL group; P = .17), pneumonitis (6.8 % in EVL group and 4.8 in SRL group; P = .38), acute rejection episode (4.1% in EVL group and 1.6% in SRL group; P = .13), proteinuria (4.1% in EVL group and 1.6% in SRL group; P = .13), renal function deterioration (2.3% in EVL group and 2.1% in SRL group; P = .91), and severe dermal eruption (2.3% in EVL group and 0.5% in SRL group; P = .14).

Conclusions

Although the overall incidence discontinuations due to side effects was higher in the EVL group, there was no greater frequency of severe side effects, such as pneumonitis, proteinuria, acute rejection episodes, renal function deterioration, or dermal eruptions.

Section snippets

Materials and Methods

From October 1999 to February 2010, 409 renal transplant patients were converted to an mTORi as primary immunosuppression: 220 to EVL (53.8%) and 189 to SRL (46.2%). Most patients were under a CNI-based immunosuppressive protocol, and all of them had received a renal allograft at least 3 months before conversion to the mTORi. We considered the reasons for all drug eliminations during the follow-up period after the mTORi introduction, comparing their incidences as well as causes.

Results

The initial mean dose was 2.95 ± 0.69 mg/d for EVL and 3.61 ± 1.51 mg/d for SRL. CNI treatment was stopped in all patients after a median of 5 days (IQR, 4–8) in the EVL and 7 days (IQR, 0–14) in the SRL group. The median follow-up was 35 months (IQR, 18–50)

mTORi treatment was prematurely eliminated due to adverse events in 112 patients. In the group treated with EVL the drug was stopped in 69 patients (31.4%); and in the SRL group in 43 patients (22.8%; P = .051). The median time between

Discussion

The first mTORi used in transplantation was SRL, also known as rapamycin (Rapamune; Wyeth Pharmaceuticals, St Davids, PA, USA). The preclinical pharmacologic profile of the new rapamycin analog, EVL, was described in 1997.3 Like SRL, this drug forms a complex with the FK-binding protein complex (FKBP-12), binding with high affinity to mTOR. mTOR is a serine-threonine kinase that is central in a complex intracellular signaling pathway involving cell growth and proliferation, cellular metabolism,

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