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Everolimus With Reduced-Dose Cyclosporine in De Novo Renal Transplant Recipients: Philippine Experience
Everolimus With Reduced-Dose Cyclosporine in De Novo Renal Transplant Recipients: Philippine Experience J.T. Li, R.A. Danguilan, C.B. Cabanayan-Casasola, Y. Talusan-Tomacruz, and E.T. Ona ABSTRACT Objective. The objective of this study was to describe the appropriate dose of everolimus to achieve target trough concentrations in standard-risk Filipino kidney transplant recipients. Methodology. We reviewed all kidney transplant recipients from December 1, 2006 to June 15, 2007 who were given everolimus (1.5 mg/d) in combination with low-dose cyclosporine (5 mg/kg/d) and prednisone but without induction therapy for their immunosuppressive doses, trough levels, as well as hematologic and blood chemistry profiles. Target everolimus trough concentration was 3– 8 ng/mL and C2 level was 1000 –1400 ng/mL for the first 3 months. Results. Among 148 patients who underwent transplantation during the study period, 26 comprised the study population but only 15 patients completed the 3-month follow-up and are the subject of this report. Their mean age was 33 years, average PRA 2%, and mean HLA mismatches 3. All were from living donors. At 7 days posttransplantation, all patients achieved or exceeded the target everolimus trough and cyclosporine C2 level. At 1 and 3 months posttransplantation the mean everolimus dose was 1.17 and 0.78 mg/d, respectively, whereas the cyclosporine dose was 195 and 148 mg/d, respectively. Three patients showed elevated alanine aminotransferase (ALT) and all patients had hypercholesterolemia after 1 month, which improved with everolimus dose reduction (half required statins). One patient experienced a Banff Grade IA acute rejection episode at 2 months posttransplantation with a serum creatinine value of 2 mg/dL after steroid pulsing. Conclusions. Most standard-risk Filipino kidney transplant recipients required a maintenance everolimus dose of 1 mg/d at 1 month. The cyclosporine dose requirement was also lower. A larger sample size is needed to provide a level of significance compared with other populations.
A
LLOGRAFT dysfunction remains a major problem following organ transplantation. It is seen in up to 40% of renal transplant recipients. In kidney transplantation, the causes of allograft dysfunction include vasculopathy and calcineurin inhibitor (CNI)-induced nephrotoxicity. The introduction of newer immunosuppressive drugs has allowed CNIsparing regimens without compromising efficacy. Everolimus (EVL; Certican by Novartis) is a proliferation signal inhibitor with a mode of action distinct from that of cyclosporine (CYA) and tacrolimus. It acts by inhibiting signals of T-cell– dependent growth factors, such as interleukin-2 (IL-2). EVL reversibly inhibits growth factor– dependent proliferation of hematopoietic as well as nonhematopoietic cells at a later stage of the cell cycle.
It has been demonstrated to be as effective as mycophenolate mofetil (MMF) with comparable rates of biopsyproven acute rejection (AR), graft loss, or death at 12 months.1 Two oral doses of EVL (1.5 mg or 3 mg daily) have been used in combination with CYA and steroids. An EVL trough of ⬎3 ng/mL seems to be needed to provide protection from AR. From the Departments of Adult Nephrology (J.T.L., R.A.D., C.B.C.-C., Y.T.-T.) and Organ Transplantation (E.T.O.), National Kidney and Transplant Institute, Quezon City, Philippines. Address reprint requests to Dr. John T. Li, Department of Adult Nephrology, National Kidney and Transplant Institute, Quezon City, Philippines. E-mail: [email protected]
© 2008 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/08/$–see front matter doi:10.1016/j.transproceed.2008.06.041
Transplantation Proceedings, 40, 2211–2213 (2008)
2211
2212
LI, DANGUILAN, CABANAYAN-CASASOLA ET AL
The 3-year results of a previous study, however, showed that patients on the EVL protocol had elevated serum creatinine levels compared with patients on MMF.2 This was believed to be due to exacerbation of CYA, nephrotoxicity; thus, CYA levels were lowered. Tedesco et al likewise found that lower target levels of CYA (measured 2 hours after intake or C2) were possible when combined with EVL.3 Moreover, when the IL-2 receptor antagonist, basiliximab, was used as induction, C2 targets could be further decreased. The reduced CYA levels combined with EVL resulted in improved graft function compared with an EVL standard-dose CYA regimen with improved AR rates. This was confirmed by Vitko et al who found that CNI blood levels reduced by 57% probably led to improved renal function.4 If an EVL-based regimen allows less exposure to CNIs while maintaining low AR rates, it would minimize the risk of calcineurin toxicity and result in good long-term graft function. This study explored the appropriate dose of EVL needed to achieve the target trough concentration in primary standard-risk Filipino kidney transplant recipients. It describes the renal function and safety issues at 3 months. METHODOLOGY We included in this study patients who underwent transplantation between December 1, 2006 and June 15, 2007 who were prescribed EVL with low-dose CYA and steroids. We collected age, gender, primary renal disease, living donor type, number of HLA mismatches, PRA screen, and date of kidney transplantation. Immunosuppression started within 24 hours of transplantation consisted of CYA at 5 mg/kg/d given in 2 divided doses and adjusted accordingly based on the target blood level (C2) of 1000 –1400 ng/mL for ⬍3 months measured using TDX. EVL was prescribed at 0.75 mg BID with the desired target trough level of 3– 8 ng/mL and prednisone at 0.5 mg/kg/d for diabetics or at 1 mg/kg/d for other patients. Steroids were tapered according to our immunosuppressive protocol. All patients received antibiotic prophylaxis with trimethoprimsulfamethoxazole, isoniazide, valacyclovir, and mycostatin. AR was treated with 3 intravenous doses of methylprednisolone. AR was defined as a ⬎25% increase in serum creatinine level from baseline, or other graft dysfunction that was confirmed by histological findings on allograft biopsy based on Banff criteria. Steroid-responsive AR was defined as a serum creatinine level that returns to within 25% of baseline within 1 week after imitiation of rejection treatment. Statistical analysis was performed using paired Student t test, Pearson chi-Square, correlation analysis, and binomial testing.
RESULTS
Among 148 patients who underwent transplantation during the study period, 26 comprised the study population but
only 15 patients completed the 3-month follow-up and had their data in this report. Their mean age was 33.07 ⫾ 11.02 years with 10 men and 5 women. The mean PRA was 2%; the mean number of HLA mismatches was 3. All grafts were from living donors. Most patients achieved or exceeded the target trough level at days 3, 7, and 14 posttransplantation. The mean EVL doses were 1.17 and 0.78 mg/d at 1 and 3 months post transplantation, respectively. The majority achieved or exceeded the target C2 level at days 3, 7, and 14. The mean CYA doses were 195 and 148 mg/d at 1 and 3 months posttransplantation, respectively (Table 1). The mean serum creatinine levels were 1.12 ⫾ 0.30 and 1.20 ⫾ 0.31 mg/dL at 1 and 3 months posttransplantation, respectively (P ⫽ .090). The mean calculated GFR was 69.36 ⫾ 16.29 and 64.09 ⫾ 13.25 mL/min for the first and third months posttransplantation period, respectively (P ⫽ .095). One patient had biopsy-proven AR (Banff IA) at 2 months posttransplantation despite adequate EVL and CYA blood levels. The rejection was steroid-resistant; hence immunosuppression was shifted to tacrolimus, mycophenolate, and steroids. Current serum creatinine level is 2 mg/dL. The mean platelet counts were 258.80 ⫾ 76.29 and 306.20 ⫾ 65.21 at 1 and 3 months posttransplantation respectively (P ⫽ .033). The mean alanine aminotransferase (ALT) levels were 86.73 ⫾ 58.36 and 53.60 ⫾ 36.37 at 1 and 3 months posttransplantation, respectively (P ⫽ .037). ALT levels were elevated in 20% of patients at 1 month corresponding with CYA and EVL drug levels exceeding the target. The ALT levels normalized after the desired drug levels were achieved. All patients had hypercholesterolemia and hypertriglyceridemia after 1 month, which improved with EVL dose reduction (half required statins). There was no hematologic abnormality. There was no delayed wound healing or lymphocoele. No infections were noted during the 3-month follow-up. There was no patient death. DISCUSSION
EVL is a new immunosuppressive drug recently introduced in the country under the class of proliferation signal inhibitors. Due to its equivalent efficacy with conventional immunosuppression consisting of CYA, mycophenolate, and steroids as well as its economic impact due to lower CYA dose requirements, our Transplant Unit explored the use of this promising drug. The results of this study showed that low-dose CYA in combination with EVL and steroids was effective in preventing AR in standard-risk primary Filipino transplant recipients. This was similar to the studies done by Vitko et al.1
Table 1. Mean Dose of Immunosuppressive Drugs Immunosuppressive Drugs
D7
D 14
Mo 1
Mo 3
EVL (mg/d) CYA (mg/d)
1.47 ⫾ 0.13 180 ⫾ 122.91
1.53 ⫾ 0.44 226.67 ⫾ 84.23
1.17 ⫾ 0.58 195 ⫾ 52.78
0.78 ⫾ 0.31 148.33 ⫾ 37.16
EVEROLIMUS WITH CYA
At starting dose of EVL at 1.5 mg/d, 92% of patients achieved a target trough by the first week posttransplantation whereas 42% exceeded it. Only 1 patient was below target (⬍2 ng/mL). By 1 month, 47% of patients exceeded the target trough so that the mean EVL dose was reduced to 1.17 ⫾ 0.58 mg/d compared with 1.47 ⫾ 0.13 mg/d at the first week posttransplantation. At the third month posttransplantation, the mean EVL dose was reduced further to 0.78 ⫾ 0.31 mg/d. This represented a 33% reduction in the EVL dose. The elevated EVL trough obtained at this time correlated with the elevated ALT and cholesterol levels, which improved with reduction in the EVL trough. This means that by the first month posttransplantation, the EVL dose could be reduced to 1.25 mg/d and decreased further by 3 months to 1 mg/d. This would prevent the adverse effects that occurred in our patients. At the first week posttransplantation, the CYA level was at target in 55% of patients, and exceeded the target in 36%. The same patient who had a low EVL trough in the first week also had a low CYA C2 level. By the first month, 60% of the patients were at target, whereas 40% exceeded the target C2 level. The mean dose of CYA was 195 ⫾ 52 mg/d at 1 month compared with 180 ⫾ 122 mg/d. At the third month, the mean CYA dose decreased to 148.33 ⫾ 37 mg/d. This represented a 24% decrease in the CYA dose.
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This means that by the third month, the CYA dose could be reduced from 180 mg/d to 150 mg/d. This descriptive study has many limitations. We recommend a randomized controlled trial with a larger population and longer follow-up to assess the long-term effects as well as cost-effectiveness of this new immunosuppressive drug. In conclusion, among Filipino kidney transplant recipients with standard risk, lower maintenance EVL and CYA doses were required than are currently recommended. EVL was well tolerated although all patients developed hyperlipidemia. REFERENCES 1. Vitko S, Margreiter R, Weimar W, et al: Everolimus (Certican) 12-month safety and efficacy versus mycophenolate mofetil in de novo renal transplant recipients. Transplantation 78:1532, 2004 2. Lorber MI, Mulgaonkar S, Butt KMH, et al: Everolimus versus mycophenolate mofetil in the prevention of rejection in de novo renal transplant recipients: a 3 year randomized, multicenter, phase III study. Transplantation 80:244, 2005 3. Tedesco H, Ambuhl P, Lorber MI, et al: Improved renal functioning following cyclosporine dose reduction in maintenance renal transplant recipients taking everolimus (certican). Presented at the American Transplant Congress, Washington, DC, April 2002 4. Vitko S, Tedesco H, Eris J, et al: Everolimus with optimised cyclosporine dosing in renal transplant recipients: 6-month safety and efficacy results of two randomised studies. Am J Transplant 4:626, 2004
A
LLOGRAFT dysfunction remains a major problem following organ transplantation. It is seen in up to 40% of renal transplant recipients. In kidney transplantation, the causes of allograft dysfunction include vasculopathy and calcineurin inhibitor (CNI)-induced nephrotoxicity. The introduction of newer immunosuppressive drugs has allowed CNIsparing regimens without compromising efficacy. Everolimus (EVL; Certican by Novartis) is a proliferation signal inhibitor with a mode of action distinct from that of cyclosporine (CYA) and tacrolimus. It acts by inhibiting signals of T-cell– dependent growth factors, such as interleukin-2 (IL-2). EVL reversibly inhibits growth factor– dependent proliferation of hematopoietic as well as nonhematopoietic cells at a later stage of the cell cycle.
It has been demonstrated to be as effective as mycophenolate mofetil (MMF) with comparable rates of biopsyproven acute rejection (AR), graft loss, or death at 12 months.1 Two oral doses of EVL (1.5 mg or 3 mg daily) have been used in combination with CYA and steroids. An EVL trough of ⬎3 ng/mL seems to be needed to provide protection from AR. From the Departments of Adult Nephrology (J.T.L., R.A.D., C.B.C.-C., Y.T.-T.) and Organ Transplantation (E.T.O.), National Kidney and Transplant Institute, Quezon City, Philippines. Address reprint requests to Dr. John T. Li, Department of Adult Nephrology, National Kidney and Transplant Institute, Quezon City, Philippines. E-mail: [email protected]
© 2008 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/08/$–see front matter doi:10.1016/j.transproceed.2008.06.041
Transplantation Proceedings, 40, 2211–2213 (2008)
2211
2212
LI, DANGUILAN, CABANAYAN-CASASOLA ET AL
The 3-year results of a previous study, however, showed that patients on the EVL protocol had elevated serum creatinine levels compared with patients on MMF.2 This was believed to be due to exacerbation of CYA, nephrotoxicity; thus, CYA levels were lowered. Tedesco et al likewise found that lower target levels of CYA (measured 2 hours after intake or C2) were possible when combined with EVL.3 Moreover, when the IL-2 receptor antagonist, basiliximab, was used as induction, C2 targets could be further decreased. The reduced CYA levels combined with EVL resulted in improved graft function compared with an EVL standard-dose CYA regimen with improved AR rates. This was confirmed by Vitko et al who found that CNI blood levels reduced by 57% probably led to improved renal function.4 If an EVL-based regimen allows less exposure to CNIs while maintaining low AR rates, it would minimize the risk of calcineurin toxicity and result in good long-term graft function. This study explored the appropriate dose of EVL needed to achieve the target trough concentration in primary standard-risk Filipino kidney transplant recipients. It describes the renal function and safety issues at 3 months. METHODOLOGY We included in this study patients who underwent transplantation between December 1, 2006 and June 15, 2007 who were prescribed EVL with low-dose CYA and steroids. We collected age, gender, primary renal disease, living donor type, number of HLA mismatches, PRA screen, and date of kidney transplantation. Immunosuppression started within 24 hours of transplantation consisted of CYA at 5 mg/kg/d given in 2 divided doses and adjusted accordingly based on the target blood level (C2) of 1000 –1400 ng/mL for ⬍3 months measured using TDX. EVL was prescribed at 0.75 mg BID with the desired target trough level of 3– 8 ng/mL and prednisone at 0.5 mg/kg/d for diabetics or at 1 mg/kg/d for other patients. Steroids were tapered according to our immunosuppressive protocol. All patients received antibiotic prophylaxis with trimethoprimsulfamethoxazole, isoniazide, valacyclovir, and mycostatin. AR was treated with 3 intravenous doses of methylprednisolone. AR was defined as a ⬎25% increase in serum creatinine level from baseline, or other graft dysfunction that was confirmed by histological findings on allograft biopsy based on Banff criteria. Steroid-responsive AR was defined as a serum creatinine level that returns to within 25% of baseline within 1 week after imitiation of rejection treatment. Statistical analysis was performed using paired Student t test, Pearson chi-Square, correlation analysis, and binomial testing.
RESULTS
Among 148 patients who underwent transplantation during the study period, 26 comprised the study population but
only 15 patients completed the 3-month follow-up and had their data in this report. Their mean age was 33.07 ⫾ 11.02 years with 10 men and 5 women. The mean PRA was 2%; the mean number of HLA mismatches was 3. All grafts were from living donors. Most patients achieved or exceeded the target trough level at days 3, 7, and 14 posttransplantation. The mean EVL doses were 1.17 and 0.78 mg/d at 1 and 3 months post transplantation, respectively. The majority achieved or exceeded the target C2 level at days 3, 7, and 14. The mean CYA doses were 195 and 148 mg/d at 1 and 3 months posttransplantation, respectively (Table 1). The mean serum creatinine levels were 1.12 ⫾ 0.30 and 1.20 ⫾ 0.31 mg/dL at 1 and 3 months posttransplantation, respectively (P ⫽ .090). The mean calculated GFR was 69.36 ⫾ 16.29 and 64.09 ⫾ 13.25 mL/min for the first and third months posttransplantation period, respectively (P ⫽ .095). One patient had biopsy-proven AR (Banff IA) at 2 months posttransplantation despite adequate EVL and CYA blood levels. The rejection was steroid-resistant; hence immunosuppression was shifted to tacrolimus, mycophenolate, and steroids. Current serum creatinine level is 2 mg/dL. The mean platelet counts were 258.80 ⫾ 76.29 and 306.20 ⫾ 65.21 at 1 and 3 months posttransplantation respectively (P ⫽ .033). The mean alanine aminotransferase (ALT) levels were 86.73 ⫾ 58.36 and 53.60 ⫾ 36.37 at 1 and 3 months posttransplantation, respectively (P ⫽ .037). ALT levels were elevated in 20% of patients at 1 month corresponding with CYA and EVL drug levels exceeding the target. The ALT levels normalized after the desired drug levels were achieved. All patients had hypercholesterolemia and hypertriglyceridemia after 1 month, which improved with EVL dose reduction (half required statins). There was no hematologic abnormality. There was no delayed wound healing or lymphocoele. No infections were noted during the 3-month follow-up. There was no patient death. DISCUSSION
EVL is a new immunosuppressive drug recently introduced in the country under the class of proliferation signal inhibitors. Due to its equivalent efficacy with conventional immunosuppression consisting of CYA, mycophenolate, and steroids as well as its economic impact due to lower CYA dose requirements, our Transplant Unit explored the use of this promising drug. The results of this study showed that low-dose CYA in combination with EVL and steroids was effective in preventing AR in standard-risk primary Filipino transplant recipients. This was similar to the studies done by Vitko et al.1
Table 1. Mean Dose of Immunosuppressive Drugs Immunosuppressive Drugs
D7
D 14
Mo 1
Mo 3
EVL (mg/d) CYA (mg/d)
1.47 ⫾ 0.13 180 ⫾ 122.91
1.53 ⫾ 0.44 226.67 ⫾ 84.23
1.17 ⫾ 0.58 195 ⫾ 52.78
0.78 ⫾ 0.31 148.33 ⫾ 37.16
EVEROLIMUS WITH CYA
At starting dose of EVL at 1.5 mg/d, 92% of patients achieved a target trough by the first week posttransplantation whereas 42% exceeded it. Only 1 patient was below target (⬍2 ng/mL). By 1 month, 47% of patients exceeded the target trough so that the mean EVL dose was reduced to 1.17 ⫾ 0.58 mg/d compared with 1.47 ⫾ 0.13 mg/d at the first week posttransplantation. At the third month posttransplantation, the mean EVL dose was reduced further to 0.78 ⫾ 0.31 mg/d. This represented a 33% reduction in the EVL dose. The elevated EVL trough obtained at this time correlated with the elevated ALT and cholesterol levels, which improved with reduction in the EVL trough. This means that by the first month posttransplantation, the EVL dose could be reduced to 1.25 mg/d and decreased further by 3 months to 1 mg/d. This would prevent the adverse effects that occurred in our patients. At the first week posttransplantation, the CYA level was at target in 55% of patients, and exceeded the target in 36%. The same patient who had a low EVL trough in the first week also had a low CYA C2 level. By the first month, 60% of the patients were at target, whereas 40% exceeded the target C2 level. The mean dose of CYA was 195 ⫾ 52 mg/d at 1 month compared with 180 ⫾ 122 mg/d. At the third month, the mean CYA dose decreased to 148.33 ⫾ 37 mg/d. This represented a 24% decrease in the CYA dose.
2213
This means that by the third month, the CYA dose could be reduced from 180 mg/d to 150 mg/d. This descriptive study has many limitations. We recommend a randomized controlled trial with a larger population and longer follow-up to assess the long-term effects as well as cost-effectiveness of this new immunosuppressive drug. In conclusion, among Filipino kidney transplant recipients with standard risk, lower maintenance EVL and CYA doses were required than are currently recommended. EVL was well tolerated although all patients developed hyperlipidemia. REFERENCES 1. Vitko S, Margreiter R, Weimar W, et al: Everolimus (Certican) 12-month safety and efficacy versus mycophenolate mofetil in de novo renal transplant recipients. Transplantation 78:1532, 2004 2. Lorber MI, Mulgaonkar S, Butt KMH, et al: Everolimus versus mycophenolate mofetil in the prevention of rejection in de novo renal transplant recipients: a 3 year randomized, multicenter, phase III study. Transplantation 80:244, 2005 3. Tedesco H, Ambuhl P, Lorber MI, et al: Improved renal functioning following cyclosporine dose reduction in maintenance renal transplant recipients taking everolimus (certican). Presented at the American Transplant Congress, Washington, DC, April 2002 4. Vitko S, Tedesco H, Eris J, et al: Everolimus with optimised cyclosporine dosing in renal transplant recipients: 6-month safety and efficacy results of two randomised studies. Am J Transplant 4:626, 2004