Department of Internal Medicine, Medical Clinic III-Hematology, Oncology, Palliative Medicine, University of Rostock, Ernst-Heydemann-Strasse 6, Rostock, Germany.
Biol Blood Marrow Transplant. 2012 Jul;18(7):1061-8. doi: 10.1016/j.bbmt.2011.12.522. Epub 2011 Dec 16.
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.
依维莫司（RAD001）是一种 mTOR 抑制剂，已成功用作实体器官移植中的免疫抑制剂。在异基因造血干细胞移植（HSCT）中的数据有限。本研究旨在调查 RAD001 在犬异基因 HSCT 模型中的药代动力学、安全性和疗效。首先，在健康犬中进行 RAD001 的药代动力学研究，以确定合适的剂量。确定 0.25 mg RAD001 每日两次与 15 mg/kg 环孢素 A（CsA）每日两次联合使用作为合适的起始剂量，以口服给药时达到 RAD001 的目标范围（3-8 μg/L）。随后，用 2 Gy 全身照射（TBI）对 10 只犬进行移植预处理，并使用 0.25 mg RAD001 每日两次和 15 mg/kg CsA 每日两次进行移植前和移植后免疫抑制。10 只移植犬中有 7 只在整个研究期间维持起始 RAD001 剂量。对于其余 3 只犬，需要调整剂量。RAD001 随时间的积累并未发生。所有犬最初均植入。5 只犬最终排斥移植物（第 10、10、13、27 和 56 周）。2 只犬因肺炎而死亡（第 8 和 72 周），但在此之前一直处于嵌合状态。总胆固醇从 HSCT 前的中位数 4.1 mmol/L（3.5-5.7 mmol/L）升高至 HSCT 后第 21 天的 6.0 mmol/L（5.0-8.5 mmol/L），但始终在正常范围内。肌酐和甘油三酯值的变化未观察到。长期植入率低于西罗莫司/CsA 和霉酚酸酯（MMF）/CsA 方案。与 MMF/CsA 相比，RAD001/CsA 导致血小板计数中位数降至 2×10(9)/L（范围：0-21×10(9)/L）和血小板恢复时间更长（范围：14-24 天）。与 MMF/CsA 免疫抑制相比，RAD001/CsA 中 CsA c(2h)水平显著升高，但 c(0h)和 0 至 12 小时的 AUC(0-12h)值没有差异。总之，由 RAD001 和 CsA 组成的免疫抑制耐受性良好，但在犬非清髓性 HSCT 方案中不如其他已建立的免疫抑制剂有效。因此，我们的研究不支持在这种情况下将 RAD001/CsA 作为标准实践应用。
