Clinical Experience with Everolimus (Certican): Optimizing Dose and Tolerability

Abstract

Background. 

Everolimus (Certican), a novel proliferation signal inhibitor, allows calcineurin inhibitor dose reduction in transplant patients, minimizing risk of nephrotoxicity without loss of immunosuppressive efficacy. As a result of its mode of action, this class of agent (i.e., everolimus and sirolimus) is associated with certain adverse events (e.g., lymphocele, arthralgia, edema and hyperlipidemia).

Methods. 

Three case studies from within an everolimus Phase III trial (A2306) are presented with the aim of illustrating how treatment-related adverse events can be managed.

Results. 

The combination of everolimus with reduced-exposure cyclosporine was efficacious in these patients. One experienced mild acute rejection that was managed with steroid boluses. All have acceptable graft function during follow-up to date. Moderate lymphocele either resolved spontaneously or was easily managed by povidine-iodine instillations. One patient developed serious early lymphocele that, unusually, required surgical intervention. Everolimus dose reduction or withdrawal was not necessary to effectively manage lymphocele of any severity. A case of bilateral multiple arthralgia was effectively managed with everolimus dose reduction, but still maintained everolimus trough blood levels at approximately 3 ng/ml. Eyelid and ankle edemas were also easily managed with low dose furosemide, preferably coupled with cyclosporine and everolimus dose reduction. Hyperlipidemia responded to statin therapy.

Conclusions. 

Everolimus-related adverse events can be effectively managed either with other treatments or, where necessary, by everolimus dose reduction, without loss of efficacy. Discontinuing everolimus therapy is generally not necessary.

Everolimus (Certican, Novartis Pharma AG, Basel, Switzerland), a novel proliferation signal inhibitor, is indicated in combination with the calcineurin inhibitor (CNI) cyclosporine (CsA; Neoral) for the prevention of organ rejection in renal transplant patients (¹). The efficacy and safety profile of everolimus was originally evaluated in conjunction with full doses of CsA, but the synergistic relationship between these two agents has allowed more recent trials to be conducted with reduced-exposure CsA, thus lowering risk of CNI-induced nephrotoxicity (^2–4).

The most frequently occurring everolimus-related adverse events are similar to those associated with other immunosuppressive therapies (e.g., infection), but some side effects are more characteristic of proliferation signal inhibitors. For example, the antiproliferative action of everolimus can lead to reduced healing of lymphatic channels that are divided during transplant surgery. Lymphatic leak can then result in the formation of lymphocele. In clinical trials, the rate of lymphocele in renal transplant patients receiving everolimus 1.5–3.0 mg/day with low-dose CsA was 6.4–15.2% at 6 months (²). In a pivotal trial of sirolimus 2.0–5.0 mg/day, it was 12–13% (⁵). Antiproliferative immunosuppression can also be a factor in the development of arthralgia and edema.

The present paper details three case studies from within the clinical experience of everolimus in kidney transplantation at the Ramón y Cajal Hospital in Madrid, Spain. The cases illustrate how everolimus can be successfully employed in combination with reduced-exposure CsA in a variety of donor–recipient age combinations (e.g., “old-for-old,” “young-for-young”) but importantly they also provide some practical guidance on how physicians can manage some class-specific adverse events, such as arthralgia, edema and lymphocele.

Study A2306

The three patients in these case studies were treated as part of a Phase III, 1-year, multicenter, randomized, open-label, parallel group trial in de novo renal transplant recipients receiving either everolimus 1.5 mg/day (112 patients) or 3.0 mg/day (125 patients) in combination with low-dose CsA for microemulsion (Neoral), and corticosteroids (^{2, 3}).

The protocol-recommended target ranges for blood levels of CsA measured 2 hr after dose administration (C₂) were: 1200 ng/ml at weeks 0–4, 800 ng/ml at weeks 5–8, 600 ng/ml at weeks 9–12, and 400 ng/ml thereafter. Target trough blood levels for everolimus were 3 ng/ml or greater (⁶).

Case 1: “Old-for-Old” Patient with Ankle Edema and Arthralgia

A 60-year-old female with chronic renal failure secondary to polycystic disease received a kidney transplant in February 2002 from a 64-year-old male donor who died after a cerebral hemorrhage. The patient also presented with arterial hypertension and was moderately overweight (body mass index [BMI] 27 kg/m²). The kidney graft functioned immediately after transplantation and the patient received CsA 4.0 mg/kg/12 hr, everolimus 0.75 mg bid (1.5 mg/day), and corticosteroids. Everolimus trough blood levels were 10 ng/ml at day 7, decreasing over the next 5 months to 4–6 ng/ml (probably as a result of decreased CsA dosing; Fig. 1A). CsA C₂ levels were close to the recommended target ranges over 2 years of follow-up (Fig. 1B).

FIGURE 1.: Case 1. (A) Everolimus dose adjustment to relieve arthralgia in an “old-for-old” renal transplant recipient. (B) Corresponding cyclosporine (CsA) C₂ levels.

Serum creatinine was highest in the first 2 months posttransplantation, reflecting an acute rejection episode (see below). However, by month 3 graft function stabilized somewhat; serum creatinine declined to 2.3 mg/dL, with further improvements over the first year to reach 2.0 mg/dL. Following reduction of CsA (1.4 mg/kg/day) and everolimus (1.0 mg/day) doses, serum creatinine levels decreased to 1.5 mg/dL during the second year posttransplantation.

Adverse Events

One week posttransplant the patient presented with bilateral ankle edema. On day 10 she received oral furosemide 40 mg/day, which was increased to 80 mg/day without significant improvement of edema. Venous problems were excluded, while serum creatinine levels were elevated (2.2–2.4 mg/dL). By day 37, serum creatinine levels had increased to 3.5 mg/dL and urine output decreased. The patient was diagnosed with acute rejection, which resolved quickly following steroid boluses. Serum creatinine levels subsequently improved (2.3 mg/dL) and leg edema was classed as moderate.

At month 5, the patient noticed bilateral symmetric multiple arthralgia in her knees, ankles, and elbows, which progressively worsened. This condition was possibly related to everolimus. At this time, CsA and prednisone doses were very low. At month 6, everolimus dose was decreased to 1.0 mg/day, leading to improvement in edema and arthralgia.

At month 6, the patient again received furosemide treatment for bilateral leg edema. After 18 months of treatment, the patient had minimal bilateral ankle edema, no arthralgia, and was stabilized on everolimus 1.0 mg/day (trough blood levels 3–4 mg/dL), and furosemide 40 mg/day.

During the study, mild lymphocele was detected. It had no impact on graft function and was conservatively managed. The patient’s blood lipid levels remained within the normal range throughout 2 years of treatment.

Clinical Implications

This “old-for-old” transplant recipient (donor >50 years) showed progressive graft function improvement after CsA and everolimus dose minimization. Previous experience in Spain indicates that mean serum creatinine levels at 1-year posttransplantation are significantly higher in patients who receive kidneys from donors over 60 years of age (2.06 mg/dL) compared with those who receive organs from donors under 60 years (1.60 mg/dL) (⁷). Slightly elevated serum creatinine is acceptable in the “old-for-old” setting, so a 1-year serum creatinine of 2.0 mg/dL is a good outcome for this patient. Although mild acute rejection did occur, it was successfully treated with steroid pulses.

Other adverse events were also managed successfully. Bilateral multiple arthralgia was easily controlled by everolimus dose reduction with trough blood levels being maintained around 3 ng/ml. Peripheral edema resolved with low-dose furosemide, coupled with CsA and everolimus dose reduction. Mild lymphocele improved without the need for treatment.

Case 2: “Young-for-young” Patient with Eyelid Edema and Lymphocele

A 40-year-old female with chronic renal failure secondary to polycystic disease received a kidney transplant in March 2002 from a 40-year-old female donor who had died after a cerebral hemorrhage. The patient was underweight with a BMI of 21 kg/m². The kidney graft functioned immediately after transplantation and the patient received CsA 4.0 mg/kg/12 hr, everolimus 1.5 mg bid (3.0 mg/day), and corticosteroids.

During the first 2 months posttransplantation, everolimus trough blood levels were approximately 7 ng/ml. Except for month 3, everolimus trough blood levels were maintained within a 3–8 ng/ml range (Fig. 2A). CsA C₂ levels were within the recommended target ranges during the first month (1000–1400 ng/ml), with levels decreasing to 800 ng/ml with graft improvement. From months 3 to 5, C₂ levels were above the target range of 550–650 ng/ml (1000–1200 ng/ml), and necessary dose reductions to 2.0 mg/kg were made. Thereafter, CsA C₂ levels were maintained at the lower limit of the target range (350 ng/ml) (Fig. 2B).

FIGURE 2.: Case 2. (A) Everolimus dose adjustment to help relieve cyclosporine (CsA)-related nephrotoxicity and edema in a “young-for-young” renal transplant recipient. (B) Corresponding CsA C₂ levels.

Good renal function was demonstrated during the 2 years posttransplantation. The best graft functioning was observed at 2 years when after 18 months’ of CsA and everolimus dose optimization, serum creatinine was 1.3 mg/dL. Creatinine clearance was maintained between 51–57 ml/min during the 2-year period. The patient experienced no rejection episodes.

Adverse Events

At 1 month posttransplantation, the patient was admitted to hospital with lymphocele and impaired graft function associated with everolimus-enhanced CsA nephrotoxicity. The patient was receiving CsA 7.0 mg/kg/day (C₂ levels, 1400 ng/ml; target range, 550–650 ng/ml), and everolimus 3.0 mg/day. By discharge, CsA was reduced to 4.0 mg/kg/day (C₂ levels, ≈800 ng/ml) and everolimus to 2.5 mg/day. Povidone-iodine instillations were used to treat the lymphocele (⁸).

At month 3, everolimus blood trough level was 13.4 ng/ml and bilateral eyelid edema developed, becoming significant by month 5 (⁹). Progressive improvement was seen after everolimus dose reductions to 1.5 mg/day (month 5), and then to 1.0 mg/day (month 7). During this time, everolimus trough blood levels were maintained at 3.3–3.8 ng/ml. Eyelid edema was minimal during the second year posttransplantation.

The patient developed hyperlipidemia soon after transplantation (total cholesterol >360 mg/dL at month 3). At month 4, the patient was prescribed atorvastatin 10 mg/day. Total cholesterol fell below the target range (240 mg/dL) at month 6, but subsequently rose again at month 24, requiring an increase in atorvastatin dose to 15 mg/day.

Clinical Implications

This 40-year-old transplant recipient showed good initial graft function, she had no acute rejection episodes, but experienced CsA nephrotoxicity at 5 weeks. Everolimus and CsA act synergistically with regard to immunosuppression and nephrotoxicity; therefore, monitoring and dose optimization is necessary to minimize risk of toxicity. Toxic effects can be reduced by CsA and, possibly, everolimus dose reduction.

Bilateral eyelid edema is a well-described complication following treatment with the proliferation signal inhibitor sirolimus. It is usually managed by discontinuing sirolimus (⁹). In this case, clinically significant bilateral eyelid edema resolved after everolimus dose reduction, but with blood trough levels maintained around 3 ng/ml. Discontinuation of everolimus was not necessary in this case. Moderate lymphocele was also easily managed, resolving after povidone-iodine instillations (⁸). Moderate hypercholesterolemia was controlled with standard dose statin therapy. The patient had no wound healing problems, hypertension, or proteinuria.

Case 3: Old Kidney for a Younger Adult Patient with Bilateral Leg Edema and Early Lymphocele

A 46-year-old female with chronic renal failure secondary to polycystic disease received a kidney transplant in June 2002 from a 60-year-old female donor who died after methanol intoxication. The patient presented with well-controlled arterial hypertension needing two antihypertensive drugs, normal weight, normal BMI (23 kg/m²), and normoglycemia. The kidney graft functioned immediately after transplantation and the patient received CsA 4.0 mg/kg/12 hr, everolimus 0.75 mg bid (1.5 mg/day), and corticosteroids.

Everolimus dose remained unchanged throughout 2 years of follow-up. Initially, on day 7, everolimus trough blood levels were slightly high (7 ng/ml), but thereafter they were then maintained at 3–5 ng/ml (Fig. 3A). CsA C₂ levels remained within recommended target ranges during the first 2 weeks posttransplantation (Fig. 3B). Serum creatinine levels were 1.8 mg/dL at month 3, 2.1 mg/dL at 1 year, and 2.0 mg/dL at 2 years.

FIGURE 3.: Case 3. (A) Everolimus dose in a younger adult receiving a kidney from an old donor. (B) Corresponding cyclosporine (CsA) C₂ levels.

Adverse Events

On day 18 posttransplantation, the patient presented with bilateral leg edema and deterioration in graft function. Furthermore, on abdominal examination, a 15 × 15 cm soft mass (early lymphocele) was identified near the renal graft. CsA dose was reduced below the target range to encourage graft function (Fig. 3B), but everolimus dose was not changed. Percutaneous drainage was performed for lymphocele. Conservative management with povidone-iodine instillations was unsuccessful. Some weeks later, a CT scan revealed an incompletely drained multiloculated collection adjacent to the graft. Lymphocele was finally resolved with laparoscopic surgical intervention. On discharge from hospital the patient had good graft function and mild bilateral leg edema. By 4 months posttransplant, CsA C₂ levels were returned to within the target range (350–450 ng/ml) (Fig. 3B).

Pretransplant total cholesterol was 220 mg/dL. Moderate hypercholesterolemia was diagnosed 1 month posttransplant (total cholesterol 248 mg/dL); however, treatment with atorvastatin was only initiated at 2 years when elevated cholesterol levels had not resolved spontaneously (total cholesterol 280 mg/dL). Arterial hypertension (present before transplant) was well controlled (under 140/85 mmHg) with losartan 50 mg/day and atenolol 100 mg/day.

Clinical Implications

This 46-year-old transplant recipient had stable graft function, with long-term serum creatinine levels around 2.0 mg/dL and no acute rejection episodes. As previously noted, this is an acceptable level of graft function for an organ that has been implanted from an elderly donor (⁷).

Importantly, the patient experienced early serious lymphocele that required surgical intervention. Although some patients who receive everolimus may develop early massive lymphocele that requires surgery, everolimus dose reduction or complete withdrawal is not necessary. Surgery for lymphocele is not common, this is only the second case where surgery has been necessary at the Ramón y Cajal Hospital. Hyperlipidemia and hypertension were easily controlled with standard medication. The patient had no wound healing problems or proteinuria.

Lessons Learnt from Clinical Experience

These three cases support the efficacy of everolimus combined with reduced-exposure CsA as an immunosuppressant regimen for renal transplant recipients, whatever the age of the donated organ. Effective therapeutic drug monitoring with doses adjusted to achieve blood levels within target ranges helps to minimize adverse events such as CNI-mediated nephrotoxicity. Everolimus-related adverse events do occur, but as the above experiences show, they can be effectively managed.

Due to its mode of action, everolimus is associated with an increased incidence of mild or moderate lymphocele. During the A2306 clinical trial, 17 patients (15.2%) in the everolimus 1.5 mg/day group and eight patients (6.4%) in the 3.0 mg/day group exhibited lymphocele after 6 months of therapy (²). Clinical experience shows that mild lymphocele can resolve itself, while moderate lymphocele usually responds to povidine-iodine. Some patients who develop serious, early massive lymphocele require surgical intervention, but even then everolimus dose reduction or withdrawal is not necessary. Lymphocele has also been reported in patients receiving sirolimus, another proliferation signal inhibitor. In a recent retrospective study of renal transplant recipients, 15.8% (56/354) of patients who had received sirolimus/CsA/steroid required treatment for lymphocele compared with 4.4% (6/136) of those prescribed CsA/steroid/with or without azathioprine (P< 0.001) (¹⁰). Drainage procedures were required in 35 of the sirolimus-treated patients, while 21 required surgery.

Unlike lymphocele, the presentation of arthralgia or edema may require everolimus dose reduction, but generally it is still possible to maintain everolimus trough blood levels within the optimal therapeutic window (3–8 ng/ml). Edema primarily requires the addition of a diuretic to the patient’s regimen. Edema is a class effect that is also observed in patients treated with sirolimus (⁹), so too is hyperlipidemia (¹¹). Hyperlipidemia can also be caused by CsA and corticosteroids (¹²). Elevated lipid levels can generally be managed with lipid-lowering agents, such as statins (⁶).

These three cases demonstrate that everolimus plus reduced-exposure CsA can be an efficacious immunosuppressant regimen. More importantly, however, they showed that in practice, specific adverse events that may arise from everolimus can be easily managed without discontinuation of the drug.