title: Everolimus in combination with cyclosporin a as pre- and posttransplantation immunosuppressive therapy in nonmyeloablative allogeneic hematopoietic stem cell transplantation.
abstract: 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.
authors.affiliation: Department of Internal Medicine, Medical Clinic III-Hematology, Oncology, Palliative Medicine, University of Rostock, Ernst-Heydemann-Strasse 6, Rostock, Germany. christian.junghanss@med.uni-rostock.de
authors.forename: Christian
authors.initials: C
authors.lastname: Junghanss
authors.forename: Susanne
authors.initials: S
authors.lastname: Rathsack
authors.forename: Rainer
authors.initials: R
authors.lastname: Wacke
authors.forename: Volker
authors.initials: V
authors.lastname: Weirich
authors.forename: Heike
authors.initials: H
authors.lastname: Vogel
authors.forename: Bernd
authors.initials: B
authors.lastname: Drewelow
authors.forename: Sabrina
authors.initials: S
authors.lastname: Mueller
authors.forename: Simone
authors.initials: S
authors.lastname: Altmann
authors.forename: Mathias
authors.initials: M
authors.lastname: Freund
authors.forename: Sandra
authors.initials: S
authors.lastname: Lange
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001792:Blood Platelets / Q000276:immunology / Q000473:pathology; D002784:Cholesterol / Q000097:blood; D016572:Cyclosporine / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004285:Dogs; D004338:Drug Combinations; D000068338:Everolimus; D006084:Graft Rejection / Q000097:blood / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D010976:Platelet Count; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019172:Transplantation Conditioning / Q000379:methods; D014184:Transplantation, Homologous; D014916:Whole-Body Irradiation
chemical_list: D004338:Drug Combinations; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D002784:Cholesterol; D000068338:Everolimus; D009173:Mycophenolic Acid; D020123:Sirolimus