Preliminary Experience With Conversion From Calcineurin Inhibitors to Everolimus in Cardiac Transplantation Maintenance Therapy

Sánchez-Brotons, Juan A.; Sobrino-Márquez, José Manuel; Lage-Gallé, Ernesto; Romero-Rodríguez, Nieves; Guisado, Agustín; Jiménez‐Díaz, Javier; Bénézet-Mazuecos, Juan; Arizón-Muñoz, José M.; Mogollón, María V.; Martínez, Alejandro Rodríguez

doi:10.1016/j.transproceed.2008.08.111

Cited by 6 publications

(4 citation statements)

References 9 publications

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“…In several single-dose studies, RAD c max values in the range of 15-21 mg/L and AUC values in the range of 90-115 mg/L Â h have been reported [10,11]. In contrast, RAD001 seems to have a considerably shortened half-life of 12 hours in dogs compared with 24-32 hours in humans [10][11][12]. However, in dogs given 1.5 mg RAD001 twice daily, a trough level of 3-8 mg/L can be easily achieved.…”

Section: Discussionmentioning

confidence: 99%

Everolimus in Combination with Cyclosporin A as Pre- and Posttransplantation Immunosuppressive Therapy in Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation

Junghanß

Rathsack

Wacke

et al. 2012

Biology of Blood and Marrow Transplantation

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Everolimus (RAD001) is an mTOR inhibitor that has been successfully used as an immunosuppressant in solid-organ transplantation. Data in allogeneic hematopoietic stem cell transplantation (HSCT) is limited. This study aimed to investigate pharmacokinetics, safety, and efficacy of RAD001 in a canine allogeneic HSCT model. First, pharmacokinetics of RAD001 were performed in healthy dogs in order to determine the appropriate dosing. Doses of 0.25 mg RAD001 twice daily in combination with 15 mg/kg cyclosporin A (CsA) twice daily were identified as appropriate starting doses to achieve the targeted range of RAD001 (3-8 μg/L) when orally administered. Subsequently, 10 dogs were transplanted using 2 Gy total body irradiation (TBI) for conditioning and 0.25 mg RAD001 twice daily plus 15 mg/kg CsA twice daily for pre- and posttransplantation immunosuppression. Seven of the 10 transplanted dogs were maintained at the starting RAD001 dose throughout the study. For the remaining 3 dogs, dose adjustments were necessary. RAD001 accumulation over time did not occur. All dogs initially engrafted. Five dogs eventually rejected the graft (weeks 10, 10, 13, 27, and 56). Two dogs died of pneumonia (weeks 8 and 72) but were chimeric until then. Total cholesterol rose from median 4.1 mmol/L (3.5-5.7 mmol/L) before HSCT to 6.0 mmol/l (5.0-8.5 mmol/l) at day 21 after HSCT, but remained always within normal range. Changes in creatinine and triglyceride values were not observed. Long-term engraftment rates were inferior to sirolimus/CsA and mycophenolate mofetil (MMF)/CsA regimen, respectively. RAD001/CsA caused a more pronounced reduction of platelet counts to median 2 × 10(9)/L (range: 0-21 × 10(9)/L) and longer time to platelet recovery of 21 days (range: 14-24 days) compared with MMF/CsA. CsA c(2h) levels were significantly enhanced in the RAD001/CsA regimen, but c(0h) and area under the curve from 0 to 12 hours (AUC(0-12h)) values did not differ compared with an MMF/CsA immunosuppression. In summary, immunosuppression consisting of RAD001 and CsA is well tolerated but not as efficient as with other established immunosuppressants in a canine nonmyeloablative HSCT regimen. Hence, our study does not support the application of RAD001/CsA as standard practice in this setting.

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Section: Discussionmentioning

confidence: 99%

Everolimus in Combination with Cyclosporin A as Pre- and Posttransplantation Immunosuppressive Therapy in Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation

Junghanß

Rathsack

Wacke

et al. 2012

Biology of Blood and Marrow Transplantation

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“…PSIs might therefore be promising agents for preventing rejection and PTLD development [94]. CNI minimization with PSIs or conversion from CNIs to PSIs is currently being trialed, with the additional possibility of renal function preservation [95,96]. The use of PSIs has been reported in association with pediatric PTLD [97,98].…”

Section: Prophylaxismentioning

confidence: 99%

Pediatric post-transplant lymphoproliferative disorder after cardiac transplantation

2009

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Post-transplant lymphoproliferative disorder (PTLD) is a well recognized and potentially fatal complication after pediatric cardiac transplantation. PTLD encompasses a wide spectrum, ranging from benign hyperplasia to more aggressive lymphoma. Most cases are Epstein-Barr virus (EBV)-related B-cell tumors resulting from impaired immunity due to immunosuppressive therapy. Pediatric recipients, often seronegative for EBV at transplantation, have a greater risk for PTLD than adults. The clinical presentation of PTLD varies from isolated lymphadenopathy to systemic disease; common sites involved are gastrointestinal tract, lung or airway, and cervical lesions. Timely and accurate diagnosis based on histological examination of biopsy tissue is essential for early intervention. Immunostaining for EBV and evaluation for clonality are needed. For prophylaxis when EBV viral loads are increasing or for initial treatment of early lesions or polymorphic PTLD, a reduction in immunosuppressive treatment is a key component of therapy, but caution is needed for possible rebound allograft rejection. Chemotherapy is indicated for patients with poor response to reduced immunosuppression and for highly aggressive monomorphic PTLD. The use of rituximab in combination with chemotherapy is effective. For the time being, avoiding excessive immunosuppression is the most effective strategy for reducing the incidence of PTLD. Calcineurin inhibitor (CNI) minimization with proliferation signal inhibitors (PSIs) or conversion from a CNI to a PSI might be useful for preventing both development of PTLD and allograft rejection.

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“…Conversion of maintenance thoracic transplant patients with deteriorating renal function to a PSI with CNI withdrawal may be effective (17)(18)(19)(20), but concerns about the risk of rejection mean that introduction of PSI therapy with continued but reduced CNI exposure may be the most attractive approach. However, to date, data relating to the efficacy and safety of everolimus with CNI minimization in maintenance thoracic transplant recipients are restricted to a single-arm pilot study (21) and a nonrandomized, single-center trial (22).…”

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confidence: 99%

Everolimus With Reduced Calcineurin Inhibitor in Thoracic Transplant Recipients With Renal Dysfunction: A Multicenter, Randomized Trial

et al. 2010

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Preliminary Experience With Conversion From Calcineurin Inhibitors to Everolimus in Cardiac Transplantation Maintenance Therapy

Cited by 6 publications

References 9 publications

Everolimus in Combination with Cyclosporin A as Pre- and Posttransplantation Immunosuppressive Therapy in Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation

Everolimus in Combination with Cyclosporin A as Pre- and Posttransplantation Immunosuppressive Therapy in Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation

Pediatric post-transplant lymphoproliferative disorder after cardiac transplantation

Everolimus With Reduced Calcineurin Inhibitor in Thoracic Transplant Recipients With Renal Dysfunction: A Multicenter, Randomized Trial

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