Conversion to Everolimus in Kidney Transplant Recipients: A Safe and Simple Procedure J.C. Ruiz, A. Sanchez-Fructuoso, E. Rodrigo, J. Conesa, J.G. Cotorruelo, C. Gómez-Alamillo, N. Calvo, A. Barrientos, and M. Arias ABSTRACT To date there is a substantial experience with rapamycin conversion in stable renal transplant recipients with respect to the procedure of conversion, initial doses, and target blood levels as well as adverse events, but in the case of Everolimus there is almost no experience with conversion and calcineurin inhibitor (CNI) withdrawal. We describe an initial experience among 32 renal transplant recipients who were converted to Everolimus with complete suspension of CNI in two Spanish transplant centers. Our results emphasised the procedure for conversion, the target levels, the adverse events, and the initial efficacy, over the first month after conversion. Our conclusions were that conversion from CNI to Everolimus was a simple, safe procedure with a predictable profile of adverse events, which were, in general, of mild intensity. There was a good correlation between initial dose and blood level. Initial doses of about 3 mg/d combined with rapid reduction in CNI exposure seemed to be adequate. The target range levels between 5 and 10 ng/mL seemed to be sufficient for complete CNI elimination, especially in patients also receiving antiproliferative drugs (such as mycophenolate mofetil or azathioprine) in whom levels near the lower end of the range might be adequate.

I

NHIBITORS OF MAMMALIAN target of rapamycin represent a new, promising therapeutic group of immunosuppressive drugs for solid organ transplantation. Rapamycin first, and recently Everolimus, have been incorporated to clinical practice. Since their role in clinical practice has not yet been completely established most centers prefer to defer treatment until there are toxicities of calcineurin inhibitors (CNIs), especially chronic allograft nephropathy (CAN) with or without evident nephrotoxicity or postransplant neoplasms.1,2 To date there is a substantial experience with rapamycin conversion in stable renal transplant recipients. The procedure of conversion, initial doses, and target blood levels as well as adverse events have been widely recognized.3–5 Nevertheless in the case of Everolimus, there is almost no experience with conversion and CNI withdrawal, because almost all clinical trials have been designed to maintain CNI either at normal or reduced doses, using Everolimus as a second immunosuppressant. Therefore there is minimal experience with CNI withdrawal using this drug.6,7 When Everolimus is administered concomitantly with reduced-dose cyclosporine (CsA), Everolimus trough levels above 3 ng/mL have been demonstrated to prevent acute rejection episodes. However, this exposure cannot be assumed

if CsA is completely withdrawn. In this case, higher levels should probably be considered, although a safe minimum level has not been suggested in this situation. Despite this limitation, the use of Everolimus for conversion from CNI will probably grow in the coming years. We sought to examine the best procedure for conversion as well as initial doses and optimal target levels after CNI suspension. Herein we have described an initial experience among a series of renal transplant recipients converted to Everolimus with complete suspension of CNI in two Spanish transplant centers. Our results emphasised the conversion procedure, the target levels, the adverse events, and the initial efficacy. MATERIALS AND METHODS Between March, 2005 and January, 2006, 32 renal transplant recipients were converted from a CNI-based immunosuppressive protocol to an Everolimus-based protocol for various reasons. From the H.U. Valdecilla (J.C.R., E.R., J.G.C., C.G.-A., M.A.), Santander and H. Clínico U. San Carlos (A.S.-F., J.C., N.C., A.B.), Madrid, Spain. Address reprint requests to Juan Carlos Ruiz San Millán, Nephrology Department, Valdecilla Hospital, 39008, Santander, Spain. E-mail: [email protected]

0041-1345/06/$–see front matter doi:10.1016/j.transproceed.2006.08.190

© 2006 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710

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Transplantation Proceedings, 38, 2424 –2426 (2006)

CONVERSION TO EVEROLIMUS

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Table 1. Description of Drug-Related Adverse Events Observed After Conversion Adverse Event

n (%)

Severity

Oral ulcers Dermal eruption Edemas in lower limbs Thrombocytopenia

3 (9.4) 2 (6.3) 1 (3.1) 1 (3.1)

2 mild/1 moderate 1 mild/1 moderate Mild Mild

Sixteen patients were converted due to CAN and deteriorating renal function, seven for severe vascular disease, six after the diagnosis of a malignant neoplasm, one due to thrombotic microangiopathy, one due to severe cytomegalovirus disease, and one patient with normal histology and renal function for prevention of CAN at the third month posttransplant. Conversion was performed at a median postransplant time of 81 months (4 to 160). Seventeen patients were under a CsA and 14 under a tacrolimus-based immunosuppressive regimen design: in one patient CNI had been previously eliminated. Forty-one percent of patients had received a double-drug protocol before conversion and 52%, a triple-drug protocol; only 7% were on CNI monotherapy (CsA). The conversion protocol consisted of addition of variable doses of Everolimus (between 1.5 and 4 mg/d) with a 50% reduction in CNI on the first day. A first evaluation was performed after 4 to 5 days of initiation, including blood levels of Everolimus as well as blood levels of the corresponding CNI, MPA, and serum creatinine. A second evaluation was performed on the 8 to 10 days after Everolimus introduction, evaluating the same parameters. All patients were evaluated at 1 month postconversion. We empirically, considered that sufficient target levels would be 8 to 12 ng/mL (enzyme-linked immunosorbent assay), a target considered optimal for this group of patients. When the first Everolimus level was inside the range or above 12 ng/mL, the CNI was completely withdrawn. When it was below 8 ng/mL the Everolimus dose was increased and CNI was maintained at the same dose until the second level. When mycophenolate mofetil was present the dose was reduced if it was greater than 1 g/d; azathioprine was also reduced if the dose was higher than 50 mg/d.

RESULTS

The mean initial Everolimus dose was 3.1 mg/d yielding a median initial level of 7.6 ng/mL (range ⫽ 1.6 to 28.5) with a linear correlation between initial dose and levels (r2 ⫽ .3; P ⫽ .002). CNI was withdrawn after the first level in all but two patients, in whom it was maintained until the second level, and then finally eliminated. The median second level was 6.9 ng/mL (range ⫽ 2.5 to 12.3). At 1 month after conversion the mean dose was 3.4 mg/d with a median level of 7.1 ng/mL (range ⫽ 1.5 to 14.6). The median time for CNI suspension was 6 days (2 to 21). Among the subgroup of patients receiving CsA with MPA an increase in MPA levels was observed after conversion (mean ⫽ 2.6 ⫾ 0.5 ng/mL at day 0; 2.5 ⫾ 0.6 at the first evaluation [day 4 to 5]; and 3.6 ⫾ 1.0 at the second evaluation; P ⫽ NS), despite previous dose reductions (1426 mg/d at day 0, 1101 at the first level, and 938 at the second level; P ⫽ .01). Conversely this was not observed among the subgroup of patients receiving tacrolimus (MPA levels of 2.3, 2.6, and 2.7, respectively).

Six of the 32 patients experienced drug related toxicity (18.7%): three patients, oral ulcers; two patients, dermal eruptions; one patient, lower limb edema; and one patient, thrombocytopenia. In most cases the adverse reactions were transient and of mild intensity, but in two cases (one case of oral ulcers and one of dermal eruption) they were moderate in severity and were followed by drug suspension. The remaining patients did not show any significant adverse event (Table 1). Thirty days after conversion we observed a tendency to improved renal function (1.93 ⫾ 0.13 vs 1.86 ⫾ 0.14 mg/dL of serum creatinine; P ⫽ .07), while a significant deterioration of renal function had been demonstrated in the 3 months before conversion (1.81 vs 1.93 mg/dL; P ⫽ .02). With respect to proteinuria there were no significant changes in the first month after conversion (1.62 ⫾ 0.62 g/d at day 0 vs 2.11 ⫾ 0.73 at 1 month; P ⫽ .11) despite an evident increase in the 3 months before conversion (1.35 ⫾ 0.52 3 months before conversion vs. 1.62 ⫾ 0.62; P ⫽ .03). A slight but significant decrease in serum hemoglobin was observed during the first month postconversion (13.0 ⫾ 0.31 vs 12.1 ⫾ 0.35 g/dL; P ⫽ .001). The number of patients under erythropoietin therapy did not change, although the mean doses were slightly higher after conversion (P ⫽ NS). Total leukocytes were 7328 ⫾ 413 at day 0 and 5971 ⫾ 359 at day 30 (P ⫽ .001). With respect to lipid profile, triglyceride levels were 114 ⫾ 8 and 159 ⫾ 13 mg/dL, respectively (P ⫽ .003), whereas total cholesterol levels were 198 ⫾ 10 and 218 ⫾ 11 mg/dL (P ⫽ .002). The percentage of patients treated with statins increased from 43% to 64% (P ⫽ .02). Table 2 summarizes the evolution of these metrics during the first month after conversion. DISCUSSION

Conversion from CNI to Everolimus is a simple, safe procedure with a predictable profile of adverse events, which were, in general of mild intensity. There was a good Table 2. Pre and 1-Month Postconversion Clinical and Laboratory Data

Weight (kg) Blood pressure (mm Hg) Serum Cr (mg/dL) Hemoglobin (g/dL) Leukocytes (⫻109/L) Platelets (⫻109/L) Total cholesterol (mg/dL) Triglicerides (mg/dL) 24-h urine protein excretion (mg/24 h) Mean Everolimus dose (mg/d) Mean Everolimus levels (ng/mL) Patients on CNI therapy (%) Patients on statin therapy (%) Patients on erythropoietin therapy (%) (100% darbepoietin) Mean darbepoietin dose (␮g/wk)

Pre

Post (1 mo)

P

71.2 136/80 1.93 13.0 7.3 225 198 114 1620 3.1 — 100 43 42

71.1 133/77 1.86 12.1 6.0 227 218 159 2110 3.4 7.1 0 64 37

NS NS .07 .001 .001 NS .002 .003 NS — — — .02 NS

34

37

NS

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correlation between initial drug dose and blood concentration. Initial doses around 3 mg/d with rapid reduction in CNI seemed to be adequate, probably with target range levels between 5 and 10 ng/mL necessary for complete CNI elimination, especially among patients also receiving antiproliferative drugs (such as mycophenolate mofetil or azathioprine) in whom levels near the lower end of the range might be adequate. A longer follow-up is needed for an efficacy analysis.

REFERENCES 1. Bumbea V, Kamar N, Ribes D, et al: Long-term results in renal transplant patients with allograft dysfunction after switching from calcineurin inhibitors to sirolimus. Nephrol Dial Transplant 20:2517, 2005

RUIZ, SANCHEZ-FRUCTUOSO, RODRIGO ET AL 2. Wu MS, Chang CT, Hung CC: Rapamycin in patients with chronic renal allograft dysfunction. Clin Transplant 19:236, 2005 3. Diekmann F, Budde K, Oppenheimer F, et al: Predictors of success in conversion from calcineurin inhibitor to sirolimus in chronic allograft dysfunction. Am J Transplant 4:1869, 2004 4. Letavernier E, Pe’raldi MN, Pariente A, et al: Proteinuria following a switch from calcineurin inhibitors to sirolimus. Transplantation 80:1198, 2005 5. Ruiz JC, Diekmann F, Campistol JM, et al: Evolution of proteinuria after conversion from calcineurin inhibitors (CNI) to sirolimus (SRL) in renal transplant patients: a multicenter study. Transplant Proc 37:3833, 2005 6. Nashan B, Curtis J, Ponticelli C, et al: Everolimus and reduced-exposure cyclosporine in de novo renal-transplant recipients: a three-year phase II, randomized, multicenter, open-label study. Transplantation 78:1332, 2004 7. Pascual J: Concentration-controlled everolimus (Certican): combination with reduced dose calcineurin inhibitors. Transplantation 79(suppl):S76, 2005