Version May 2024
INTRODUCTION — There are three commercially available mammalian (mechanistic) target of rapamycin (mTOR) inhibitors the US Food and Drug Administration (FDA) approved in the United States: sirolimus, everolimus, and temsirolimus. Sirolimus (rapamycin) is a macrocyclic triene antibiotic that is produced by fermentation of Streptomyces hygroscopicus. Sirolimus was discovered from a soil sample collected in Rapa Nui, which is also known as Easter Island [1]. Although it was originally developed as an antifungal agent, it was later found to have immunosuppressive (US FDA approval in 2003 for prevention of acute rejection in kidney transplantation) and antiproliferative properties that may be useful to treat or prevent proliferative diseases such as tuberous sclerosis, psoriasis, and malignancy. Temsirolimus and everolimus are both analogs of sirolimus approved for the treatment of renal cell carcinoma. Everolimus is US FDA approved for kidney and liver transplant rejection prophylaxis.
The pharmacology of the mTOR inhibitors and their use and efficacy in kidney transplant recipients will be reviewed here. A discussion of immunosuppressive therapy in kidney transplant recipients is presented separately. (See "Kidney transplantation in adults: Maintenance immunosuppressive therapy".)
MECHANISM OF ACTION — Following entry into the cytoplasm, sirolimus and everolimus bind to the FK binding protein and presumably modulate the activity of the mTOR [2]. The mTOR inhibits interleukin (IL)-2-mediated signal transduction, resulting in cell-cycle arrest in the G1-S phase [2,3]. Sirolimus and everolimus block the response of T and B cell activation by cytokines, which prevents cell-cycle progression and proliferation; by contrast, tacrolimus and cyclosporine inhibit the production of cytokines [4].
Sirolimus also appears to inhibit proliferation of smooth muscle cells [5] and, since there is activation of the sirolimus target in tuberous sclerosis lesions, may dampen the growth of angiomyolipomas with tuberous sclerosis [6]. Sirolimus may also have antimalignancy potential [7]. Temsirolimus and everolimus received approval for treatment of advanced renal cell carcinoma in 2007 and 2009, respectively. (See "Malignancy after solid organ transplantation".)
FORMULATIONS — Sirolimus is available in a 1 mg/mL oral solution (60 mL) and a 0.5, 1, and 2 mg triangular-shaped tablet. Although the oral solution and tablet are not bioequivalent, clinical equivalence has been demonstrated [3].
Everolimus is available as a 0.25, 0.5, 0.75, and 1 mg round, flat tablet.
DOSE AND ADMINISTRATION
Administration
●Sirolimus – Sirolimus is typically administered as a tablet, although a solution is available for those who are not able to swallow.
Sirolimus oral solution should be taken in the following manner:
•Empty the medication from the amber syringe into a glass or plastic container.
•Then, it should be vigorously stirred with 2 ounces of water or orange juice.
•After immediately drinking the mixture, the container should again be filled with 4 ounces of fluid and consumed immediately.
•Sirolimus should not be mixed with grapefruit juice.
•The oral solution should be protected from light and stored under refrigeration at all times to prevent degradation.
●Everolimus – Everolimus is administered as a tablet.
Dose — Clinical trials of initial immunosuppressive regimens after kidney transplant have included sirolimus as a component of a regimen that includes cyclosporine and glucocorticoids [8,9]. In these trials, a one-time loading dose of 6 or 15 mg (three times the maintenance dose), followed by a maintenance dose of either 2 or 5 mg/day, was utilized.
An initial everolimus dose of 0.75 mg given orally twice daily is recommended for adult kidney transplant patients in combination with reduced-dose cyclosporine [10].
Limited data on sirolimus and everolimus dosing are available in the geriatric and pediatric populations [3,11,12].
Dose adjustments — In clinical practice, dose adjustments for sirolimus and everolimus are made based upon several factors including concomitant administration of P450 enzyme inducers or inhibitors, hepatic insufficiency, toxicity, and/or infection [2].
Dose adjustment of sirolimus is not required in the presence of kidney function impairment [3]. By contrast, dose reductions of approximately one-third the normal maintenance dose should be used for patients with hepatic impairment.
In patients with moderate or severe hepatic impairment (Child-Pugh class B and C), the daily dose of everolimus needs to be reduced by one-half the recommended initial daily dose [10].
Close monitoring of mTOR inhibitors with whole-blood concentrations is indicated. (See 'Drug monitoring' below.)
Drug monitoring — An excellent correlation exists between trough whole-blood levels and the area under the time-concentration curve (AUC) for sirolimus and everolimus [13,14]. Routine therapeutic drug monitoring of sirolimus and everolimus blood concentrations is recommended for all patients [15].
In clinical practice, sirolimus whole-blood concentrations are being measured by both chromatographic and immunoassay methodologies. The recommended time for collection is one hour prior to the next oral dose. Whole-blood samples should be collected in tubes with ethylenediaminetetraacetic acid (EDTA) and protected from light; samples collected in this fashion are stable for 24 hours at room temperature, up to one week at 2 to 8°C, and up to three months at -20°C.
When sirolimus is used in combination with cyclosporine and prednisone, trough whole-blood sirolimus concentrations of 5 to 15 ng/mL were associated with protection from acute rejection episodes and adverse effects. Sirolimus trough concentrations >15 ng/mL have been correlated with hypertriglyceridemia, thrombocytopenia, and leukopenia. Sirolimus concentrations <5 ng/mL were associated with the occurrence of acute rejection in kidney transplant recipients [16].
When sirolimus is used with azathioprine and prednisone, higher trough concentrations may be necessary. In a clinical trial of kidney transplant recipients, sirolimus trough concentrations were maintained at 30 ng/mL for the first two months posttransplant, then reduced to 15 ng/mL thereafter. Acute rejection episodes were reported in 28 to 41 percent of patients [17,18].
Routine monitoring of everolimus trough concentrations is recommended in all patients, and the concentrations should fall within the 3 to 8 ng/mL target range [10]. Optimally, dose adjustments of everolimus should be based on trough concentrations obtained four or five days after a previous dosing change [19-23].
Steady-state concentrations — Steady-state concentrations of sirolimus occur five to seven days after initiation of therapy or a change in dose. During clinical trials, mean sirolimus whole-blood trough concentrations (determined by immunoassay) were 9 ng/mL (range, 4.5 to 14 ng/mL) and 17 ng/mL (range, 10 to 28 ng/mL) in the 2 and 5 mg treatment groups, respectively.
Steady-state concentrations of everolimus occur after four to five days in kidney transplant patients receiving 0.75 mg twice daily.
PHARMACOKINETICS
Absorption
Peak concentration — The time to peak concentration of sirolimus and everolimus is one to two hours [3].
Bioavailability — The mean bioavailability of sirolimus oral solution is 14 percent. When compared with the oral solution, sirolimus tablets have a 27 percent higher bioavailability [3]. The rate and extent of oral absorption of sirolimus may be reduced in Black patients [13].
Effects of food — The absorption of sirolimus and everolimus are altered by concurrent food intake. In 22 healthy volunteers, for example, the administration of sirolimus and a high-fat breakfast resulted in a 34 percent decrease in the maximum concentration (Cmax), a 3.5-fold increase in the time to Cmax, and a 35 percent increase in the area under the time-concentration curve (AUC) of sirolimus when compared with the fasting state [3,10]. To minimize sirolimus variability caused by food [3], we prefer to have patients take sirolimus at 8 AM, usually one to two hours after food ingestion. Everolimus should be taken consistently with or without food [10].
Distribution — The mean volume of distribution of sirolimus is 12 L/kg, with 97 percent of the agent being bound to albumin [3]. The highest concentration of sirolimus is found in red blood cells (95 percent). This is followed by plasma (3 percent), lymphocytes (1 percent), and granulocytes (1 percent); usual blood/plasma ratios are approximately 30 [4,13,14,24,25]. In animal studies, high concentrations have been found in heart, intestines, kidneys, liver, spleen, muscle, lungs, and testes. Tissue/blood ratios have usually been >20 [4].
For everolimus, plasma protein binding is approximately 74 percent in healthy subjects and in patients with moderate hepatic impairment. The apparent distribution volume from a single-dose pharmacokinetic study in maintenance kidney transplant patients is 342 to 107 L (range 128 to 589 L) [10].
Metabolism — Sirolimus and everolimus are extensively metabolized in the liver and are substrates for cytochrome P450 3A4 and P-glycoprotein [2,3,10]. The extent of metabolism of sirolimus in the intestinal wall is unknown [24,26]. Sirolimus is countertransported in the gut lumen by P-glycoprotein. These processes account for low bioavailability and high pharmacokinetic variability [4,24,26].
Metabolites contribute to <10 percent of immunosuppressive activity of the parent compound, sirolimus. Known metabolites include hydroxy sirolimus, desmethyl sirolimus, and hydroxymethyl sirolimus. Everolimus, the 40-O-(2 hydroxyethyl) derivative of sirolimus, has six predominant metabolites, all with minimal immunosuppressive activity.
Excretion — Total body clearance of sirolimus is 127 to 240 mL/hour/kg [4,13,14,27]. Large intersubject variability occurs in the oral clearance of sirolimus, which has been reported to be 45 percent higher in Black patients when compared with other patients [13].
Sirolimus and everolimus are mainly excreted in the feces, with a small percent in the urine [3,10]. The elimination half-life of sirolimus is 57 to 63 hours [4,13,24,27], which enables once-daily dosing. Everolimus has a shorter half-life of approximately 30 hours [10].
Drug interactions — Because sirolimus and everolimus are substrates for cytochrome P450 3A, the coadministration of sirolimus with cytochrome P450 3A inducers (such as some anticonvulsants, rifampin, St. John's wort) and with cytochrome P450 3A inhibitors (such as azole antifungals, nondihydropyridine calcium channel blockers, some macrolide antibiotics, grapefruit) can result in significant interactions. Therapeutic drug monitoring and dose reduction should also be considered when sirolimus or everolimus is coadministered with cannabidiol, which can increase blood levels of these agents [28]. Detail concerning mTOR inhibitor drug interactions and suggestions for their management are described in the tables (table 1 and table 2 and table 3). Additional information is available in the drug interactions program provided by UpToDate.
Cyclosporine — Concurrent administration of sirolimus and cyclosporine results in significantly higher peak/trough levels and AUC when compared with their administration four hours apart [29]. This was shown in a single-dose drug-interaction study in which sirolimus 10 mg and cyclosporine 300 mg oral soft gelatin capsules were administered either simultaneously or four hours apart [29]. When given together, the sirolimus mean Cmax and AUC were increased by 116 and 230 percent, respectively, relative to administration of sirolimus alone. Whole-blood trough levels increased by approximately 30 percent with concomitant dosing, and the time to peak levels was also shorter (1.8 versus 2.5 hours). By comparison, when sirolimus was given four hours after cyclosporine, the Cmax and AUC were increased by 37 and 80 percent, respectively, compared with administration of sirolimus alone. The mean cyclosporine Cmax and AUC were not significantly affected by sirolimus when given concomitantly or four hours after cyclosporine.
Because of these drug interactions and additive side effects (hypertriglyceridemia, possibly thrombotic thrombocytopenic purpura-hemolytic uremic syndrome [TTP-HUS]) with cyclosporine, we prefer not to use cyclosporine with sirolimus. Nevertheless, when we do use the combination of cyclosporine and sirolimus, it is usually in the setting of administering sirolimus as either rescue therapy or to help reduce cyclosporine toxicity. In this setting, it is recommended that the time of administration of sirolimus be consistent with that of the administration of cyclosporine (ie, consistently administer sirolimus at the same time as cyclosporine or four hours after the cyclosporine dose) to avoid variability in drug exposure. Serum drug concentrations should be carefully monitored.
In a single-dose study in healthy subjects, cyclosporine administered at a dose of 175 mg increased everolimus AUC by 168 percent (range 46 to 365 percent) and Cmax by 82 percent when administered with 2 mg everolimus, compared with administration of everolimus alone [10].
Tacrolimus — Although sirolimus and tacrolimus have different mechanisms of action, they share the same binding protein (FKBP-12) [2]. Initial in vitro experiments reported an antagonist effect between sirolimus and tacrolimus. However, because of the ubiquitous nature of FKBP-12, in vivo studies of pharmacologic doses of sirolimus did not reveal competitive inhibition [30].
Tacrolimus does not have the same pharmacokinetic interactions with sirolimus as cyclosporine. In a crossover study, simultaneous and separate (by four hours) administration of sirolimus and tacrolimus were compared. No significant interactions were found in pharmacokinetic parameters, including AUC and Cmax [31].
A unique form of cast nephropathy has been described in a few patients with delayed allograft function and extensive tubular damage who were being administered tacrolimus plus sirolimus [32]. Casts were histologically indistinguishable from those observed with myeloma nephropathy. (See "Kidney disease in multiple myeloma and other monoclonal gammopathies: Etiology and evaluation".)
ADVERSE EFFECTS — Sirolimus and everolimus are associated with a number of possible adverse effects including leukopenia, thrombocytopenia, anemia, hypercholesterolemia, hypertriglyceridemia, diarrhea, and others. Among kidney and pancreas-kidney transplant recipients, an increased mortality risk was associated with sirolimus- compared with non-sirolimus-containing immunosuppressive regimens. (See 'Mortality' below.)
Mortality — Sirolimus-based immunosuppression has been associated with an increased risk of posttransplant mortality when compared with calcineurin inhibitor-based strategies. A systematic review and meta-analysis of 21 randomized trials examined the risk of malignancy and death among 5876 kidney and kidney-pancreas transplant recipients treated with and without sirolimus [33]. Patients treated with sirolimus, compared with those without sirolimus, had a lower risk of malignancy (adjusted hazard ratio [HR] 0.60, 95% CI 0.39-0.93) but a higher risk of mortality (HR 1.43, 95% CI 1.21-1.71). The increased mortality among sirolimus-treated patients was driven by an increase in cardiovascular and infection-related deaths.
In an observational study of 9353 kidney transplant recipients, the use of mTOR inhibitors (either sirolimus or everolimus) was associated with a higher risk of all-cause mortality (HR 1.47, 95% CI 1.23-1.76) and death from malignancy (HR 1.37, 95% 1.09-1.71) [34].
Hematologic effects — Anemia, thrombocytopenia, and leukopenia can be observed in those administered sirolimus:
●In clinical trials, anemia has been reported in 19 to 57 percent of patients, with variability based in part on time posttransplant [3,7,35]. The combination of mycophenolate plus sirolimus may be associated with an enhanced incidence of anemia [36].
●Thrombocytopenia has been observed in 8 to 30 percent of subjects [3,7]. Reductions in platelet count are dose related and usually occur 9 to 10 days after initiation of treatment [37,38]. Normalization of platelet counts is seen within two weeks of discontinuation [37].
●Leukopenia, which does not appear to be dose related, is evident within two weeks of initiation of therapy and is reversible upon discontinuation [37,38]. In one study, among 64 patients administered sirolimus in a randomized trial (target trough concentration of 6 to 12 ng/ml), seven (11 percent) developed leukopenia [7].
Similar hematological effects have been reported with everolimus [10].
Anemia associated with mTOR inhibitors is generally mild and reversible. If a patient has anemia posttransplant, bleeding, iron deficiency, and malignancy should also be excluded (see "Anemia and the kidney transplant recipient", section on 'Pathogenesis and risk factors'). Leukopenia or thrombocytopenia associated with mTOR inhibitors may occur if the mTOR inhibitor is combined with other medications that cause leukopenia or thrombocytopenia (eg, antithymocyte globulin, valganciclovir). Close monitoring of concomitant drugs, blood counts, and symptoms and signs (fatigue, pallor, fever, signs of infection, easy bruising, bleeding) is warranted.
Hemolytic uremic syndrome/thrombotic microangiopathy — Hemolytic uremic syndrome (HUS)/thrombotic microangiopathy has been reported with the combination of cyclosporine and sirolimus immunosuppressive regimen [39-41]:
●HUS was reported in one group of 10 patients administered cyclosporine and sirolimus [39]. These patients were noted to have higher cyclosporine and sirolimus levels than those without HUS, and discontinuation of these agents resulted in reversal of HUS in most cases. Of note, the incidence of HUS at this center was lower on a regimen of cyclosporine and sirolimus when compared with historic controls on a tacrolimus- or cyclosporine-based regimen without sirolimus [39].
●In a single-center cohort study, 13 of 368 patients developed biopsy-proven thrombotic microangiopathy [40]. The incidence was highest with cyclosporine and sirolimus (20 percent, six patients), compared with other regimens, including cyclosporine plus mycophenolate, tacrolimus plus mycophenolate, and tacrolimus plus sirolimus.
●In a retrospective study, HUS was reported in five lung transplant recipients who received everolimus [42].
An increased rate of hepatic artery thrombosis, graft loss, and death has also been reported in liver transplant recipients. In two multicenter, randomized trials in de novo liver transplant recipients, the use of sirolimus in combination with either cyclosporine or tacrolimus was associated with an increased rate of hepatic artery thrombosis [3]. Furthermore, in one phase II study, the use of sirolimus and tacrolimus was associated with an increased rate of death and graft loss.
Metabolic effects — Hyperlipidemia (23 to 57 percent) and hypercholesterolemia (38 to 46 percent) are dose-related effects of sirolimus therapy that occur via the inhibition of lipoprotein lipase [7,43-45]. Similar effects are seen with everolimus [10].
Hyperlipidemia and hypertriglyceridemia should be assessed before initiating mTOR inhibitor therapy. Patients should have lipid levels checked at baseline and routinely monitored while the patient remains on treatment. Patients taking mTOR inhibitors should be educated on strategies (eg, low-fat diet, exercise) to manage hyperlipidemia or hypertriglyceridemia. Drug management may be necessary.
Long-term exposure to sirolimus may also cause deterioration of glucose metabolism and promote new-onset diabetes after transplantation. A discussion of sirolimus and posttransplant diabetes mellitus is presented separately. (See "Kidney transplantation in adults: Posttransplantation diabetes mellitus".)
Gastrointestinal system — Common gastrointestinal adverse events include constipation (28 to 36 percent), diarrhea (25 to 42 percent), dyspepsia (17 to 25 percent), nausea (25 to 36 percent), and vomiting (19 to 25 percent) [3,7,10].
Painful mouth ulcers, not related to herpes simplex virus, have been reported in some patients taking sirolimus and everolimus [10]. It is unclear if this adverse effect is dose related. In addition, oral ulcers may occur with the combination of sirolimus and mycophenolate mofetil and may be seen more frequently in glucocorticoid-avoidance protocols [46,47]. In a study cited above, among 64 patients administered sirolimus in a randomized trial (target trough concentration of 6 to 12 ng/mL), 24 (38 percent) developed aphthous ulcers [7].
Mouth sores may be managed with baking soda rinses and topical anesthetics (viscous lidocaine) or, in severe cases, dose reduction or discontinuation of the mTOR inhibitor.
Sirolimus may cause or delay healing of gastric or duodenal ulcers [48-51]. (See "Unusual causes of peptic ulcer disease", section on 'Non-NSAID medications'.)
Respiratory system — Progressive interstitial pneumonitis has been observed in a number of transplant recipients [3,7,52-56], with an incidence of 22 percent in one study [7]. Increased risk factors for pneumonitis include a late switch to sirolimus and impaired kidney function [55]. Clinical symptoms consist of dyspnea, dry cough, fever, and fatigue [54]. In one report of 24 patients, radiographic and bronchoalveolar lavage principally revealed bronchiolitis obliterans organizing pneumonia and lymphocytic alveolitis [54,55]. Complete recovery was observed in all patients within six months of sirolimus withdrawal.
Kidney function — Sirolimus nephrotoxicity can manifest in various ways that include acute kidney injury (AKI), proteinuria, prolongation of delayed allograft function, and thrombotic microangiopathy. The combination of sirolimus and cyclosporine has caused synergistic nephrotoxicity in animals and humans [53], which may be due to increased renal and whole-blood levels of cyclosporine [57] and/or the resultant increase in the fibrogenic cytokine transforming growth factor (TGF)-beta [58,59]. In addition, sirolimus inhibits P-glycoprotein-mediated efflux of cyclosporine from renal tubular epithelial cells, thereby increasing intratubular levels of cyclosporine and potentiating cyclosporine nephrotoxicity [60].
During phase III clinical trials that used combination therapy with sirolimus and cyclosporine, the mean serum creatinine concentration and glomerular filtration rates (GFRs) were increased and decreased, respectively. These effects were not observed with cyclosporine and placebo or azathioprine controls. In addition, the combination of sirolimus plus tacrolimus, compared with tacrolimus and mycophenolate regimens, is consistently associated with decreased kidney function in several prospective studies [61-64].
Kidney function and proteinuria should therefore be carefully and routinely monitored in patients treated with combination therapy with sirolimus and a calcineurin inhibitor [3].
There is also some evidence that sirolimus may be associated with delayed allograft function [32,65,66]. In a study of 144 first deceased- or living-donor kidney allograft recipients, delayed graft function was significantly more common in patients treated with rapamycin than without this agent (25 versus 9 percent) [32]. However, given that these were retrospective, nonrandomized studies, these results may reflect bias that sirolimus may have been administered because of the perception of less nephrotoxicity with this agent. Delayed graft function has not been observed with everolimus [20].
Issues related to kidney function, calcineurin inhibitor withdrawal, and sirolimus are discussed below. (See 'Use in kidney transplantation' below.)
Proteinuria — Sirolimus has also been associated with proteinuria and a glomerulonephropathy (particularly focal segmental glomerulosclerosis [FSGS]), most commonly in patients who are converted from a calcineurin inhibitor to sirolimus [7,67-80]:
●In one retrospective study of 68 kidney transplant recipients in whom sirolimus was substituted for a calcineurin inhibitor, proteinuria was assessed prior to and at 3, 6, 12, and 24 months after the substitution [71]. Compared with baseline levels (mean of 0.36 grams/day), proteinuria markedly increased at 3, 6, 12, and 24 months (1.35, 1.67, 1.27, and 1.14 grams/day, respectively). Proteinuria was reversible among the 19 patients in whom sirolimus was withdrawn (1.95 to 0.9 grams/day).
●In one study of patients converted to sirolimus, 64 percent developed proteinuria, with 30 percent of these developing FSGS [73].
●A collapsing form of FSGS has been associated with the use of sirolimus, which had been used to treat a patient with Kaposi sarcoma [69]. (See "Collapsing focal segmental glomerulosclerosis (collapsing glomerulopathy)".)
Possible mechanisms for proteinuria with sirolimus involve reduced tubular protein reabsorption [81], podocyte dysregulation [77], and overexpression of vascular endothelial growth factor that enhances cell wall permeability, leading to collapsing FSGS [69].
Conversion to an mTOR inhibitor from a calcineurin inhibitor should only occur in patients with mild proteinuria and an estimated GFR of more than 40 mL/min [80].
Mild proteinuria may be treated with angiotensin-converting enzyme (ACE) inhibitors, and heavy proteinuria may require drug discontinuation.
Other kidney disorders — A unique form of cast nephropathy has been described in a few patients with delayed allograft function and extensive tubular damage who were being administered tacrolimus plus sirolimus [32]. Casts were histologically indistinguishable from those observed with myeloma nephropathy.
AKI occurring in association with myoglobinuria and myoglobulin-appearing casts have also been reported in patients administered sirolimus [82]. Additional reports have noted an increased risk of delayed allograft function [65,66]. (See "Kidney disease in multiple myeloma and other monoclonal gammopathies: Etiology and evaluation" and 'Use in kidney transplantation' below.)
Malignancy — Posttransplant lymphoproliferative disease (PTLD) is uncommon among those administered sirolimus and cyclosporine. There is also some evidence that sirolimus may actually have antimalignancy effects (see "Malignancy after solid organ transplantation"). However, in a retrospective review of Medicare Claims Files data for transplant recipients who underwent transplant from January 2000 to September 2006, de novo use of sirolimus was associated with a 22 percent increased risk of PTLD (hazard ratio [HR] 1.22, 95% CI 1.03-1.45) [83].
Teratogenicity/effects on pregnancy and fertility — Sirolimus and everolimus are contraindicated in pregnancy, and their use should also be discontinued at least 8 to 12 weeks prior to attempted conception [84]. (See "Sexual and reproductive health after kidney transplantation", section on 'Management of immunosuppression'.)
In general, we recommend that women posttransplant who wish to conceive be switched prior to conception from sirolimus to cyclosporine or tacrolimus. Upon delivery, it is our general practice to switch the mother back to her basal immunosuppression in view of the potential benefits of the newer agents to prevent late acute rejection and chronic allograft nephropathy.
There is also some evidence that sirolimus is associated with impaired spermatogenesis. In an observational study of 95 kidney transplant patients, the total sperm count was significantly lower among those who received sirolimus (29 x 106 versus 292 x 106) [85]. In addition, patients receiving a sirolimus-based regimen had a significantly decreased fathered-pregnancy rate, compared with those administered a sirolimus-free regimen (5.9 versus 92.9 pregnancies/1000 patient-years). Thus, men who desire to father children should be informed of the risks and benefits associated with exposure to sirolimus.
Other adverse effects — In two case reports, sirolimus has been associated with the development of leukocytoclastic vasculitis [86,87]. Sirolimus is also associated with postoperative wound complications. This is discussed separately. (See "Kidney transplantation in adults: Nontransplant surgery in the kidney transplant recipient".)
There appears to be an increased incidence of angioedema in patients administered ACE inhibitors plus either sirolimus or everolimus [88,89]. This was best shown in a retrospective study of 309 patients administered either sirolimus (144) or everolimus (165), with 137 also being treated with ACE inhibitors [89]. Combined therapy was associated with a 6.6 percent incidence of angioedema, compared with a 1 to 2 percent incidence in those not being administered the combined regimen.
A large number of cutaneous adverse events can be observed with sirolimus [90,91]. In one study from France, skin disorders were reported in 79 of 80 kidney transplant patients [90]; the most frequent were acne-like eruptions (46 percent), scalp folliculitis (26 percent), hidradenitis suppurativa (12 percent), edema (55 percent), angioedema (15 percent), aphthous ulceration (60 percent), and epistaxis (60 percent). The peripheral edema associated with mTOR inhibitors may be asymmetric and in some cases may not resolve after discontinuation of the agent.
Pericardial effusion has been noted with sirolimus. Although most have been reported in cardiac transplant recipients, cases of pericardial effusion were observed in kidney transplant patients given sirolimus [92].
To date, everolimus has not been compared with sirolimus in a head-to-head trial, but, in noncomparative trials, the side effects are similar. In trials comparing mycophenolate to everolimus in conjunction with cyclosporine, the most common adverse reactions observed in the everolimus group were peripheral edema, constipation, hypertension, nausea, anemia, urinary tract infection (UTI), and hyperlipidemia [20-23].
USE IN KIDNEY TRANSPLANTATION — Sirolimus and everolimus have been utilized in a number of settings in kidney transplantation, although their use has been decreasing due to the various problems outlined above.
●Maintenance therapy – The efficacy of mTOR inhibitors for primary maintenance immunosuppressive therapy in kidney transplant recipients is well documented. However, early posttransplantation complications of sirolimus, particularly delayed allograft function, poor wound healing, adverse short-term outcomes, and an increased incidence of lymphoceles, have limited the de novo use of mTOR inhibitors at some centers. (See 'Adverse effects' above and "Kidney transplantation in adults: Nontransplant surgery in the kidney transplant recipient" and "Liver transplantation in adults: Initial and maintenance immunosuppression", section on 'Calcineurin inhibitor (CNI)-related toxicity' and "Kidney transplantation in adults: Maintenance immunosuppressive therapy", section on 'Calcineurin inhibitor-related toxicity'.)
●Glucocorticoid withdrawal – In an attempt to minimize glucocorticoid-induced morbidity, sirolimus has been administered to kidney transplant recipients in whom glucocorticoids were eventually withdrawn [61,93-98].
●Chronic kidney allograft nephropathy – A discussion of the use of sirolimus in patients with chronic kidney allograft nephropathy is discussed separately. (See "Kidney transplantation in adults: Chronic allograft nephropathy".)
●Refractory kidney transplant rejection – The efficacy of sirolimus for refractory kidney allograft rejection has been evaluated in limited preliminary studies [99]. Further study is required to better understand the role of sirolimus in this setting. (See "Kidney transplantation in adults: Treatment of acute T cell-mediated (cellular) rejection".)
●Patients at risk for cytomegalovirus (CMV) infection – A lower incidence and severity of CMV infection in transplant recipients treated with mTOR inhibitors has been observed in several clinical trials and meta-analyses [100-102]. Future trials designed to test the effect of mTOR inhibitors on CMV infection should be conducted.
●Patients with skin cancer – Sirolimus may have an antineoplastic effect among kidney transplant recipients with squamous cell carcinoma. In one trial, kidney transplant recipients with at least one cutaneous squamous cell carcinoma were randomly assigned to receive sirolimus as a substitute for calcineurin inhibitors or to maintain calcineurin inhibitor therapy [7]. Patients who were converted to sirolimus, compared with those maintained on calcineurin inhibitors, had a lower rate of new squamous cell carcinomas (22 versus 39 percent). More adverse events occurred in the sirolimus group, resulting in discontinuation of sirolimus in 23 percent of patients.
Several meta-analyses comparing outcomes in kidney transplant recipients treated with or without sirolimus have demonstrated lower rates of nonmelanoma skin cancer among patients treated with sirolimus [33,103,104].
Sirolimus has also been used for the treatment of Kaposi sarcoma after kidney transplantation [105]. (See "Malignancy after solid organ transplantation", section on 'Immunosuppression'.)
SUMMARY AND RECOMMENDATIONS
●Overview – There are two commercially available mammalian (mechanistic) target of rapamycin (mTOR) inhibitors that are US Food and Drug Administration (FDA) approved in the United States for kidney transplantation, including sirolimus and everolimus. Both have immunosuppressive and antiproliferative properties. (See 'Introduction' above.)
●Mechanism of action – Sirolimus and everolimus block the response of T and B cell activation by cytokines, which prevents cell-cycle progression and proliferation; by contrast, tacrolimus and cyclosporine inhibit the production of cytokines. (See 'Mechanism of action' above.)
●Dose and administration – Sirolimus and everolimus are extensively metabolized in the liver and are substrates for cytochrome P450 3A4 and P-glycoprotein. Dose adjustment of sirolimus is not required in the presence of kidney function impairment but is for patients with hepatic impairment. Routine therapeutic drug monitoring of sirolimus blood concentrations is recommended for all patients. The recommended time for collection is one hour prior to the next oral dose. (See 'Dose adjustments' above and 'Drug monitoring' above.)
●Drug interactions – Because sirolimus and everolimus are substrates for cytochrome P450 3A, the coadministration of sirolimus with cytochrome P450 3A inducers (such as some anticonvulsants, rifampin, St. John's wort) and with cytochrome P450 3A inhibitors (such as azole antifungals, nondihydropyridine calcium channel blockers, some macrolide antibiotics, grapefruit) can result in significant interactions. (See 'Drug interactions' above.)
●Adverse effects – Sirolimus and everolimus are associated with a number of possible adverse effects, including leukopenia, thrombocytopenia, anemia, hypercholesterolemia, hypertriglyceridemia, diarrhea, new-onset diabetes, and others. Among kidney transplant recipients, increased mortality risk has been associated with sirolimus compared with non-sirolimus-containing immunosuppressive regimens. (See 'Adverse effects' above.)
●Effects on pregnancy – Sirolimus and everolimus are contraindicated in pregnancy. (See 'Teratogenicity/effects on pregnancy and fertility' above.)
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