TWO DOSES STUDY TO COMPARE THE SAFETY OF SDZ RAD IN HEART/LUNG TRANSPLANT

本研究为随机、双盲、分层(TO 胰腺功能不全囊性纤维化与非囊性纤维化的初步诊断 囊性纤维化)，旨在测试耐受性的交叉试验， SDZ RAD的安全性、药代动力学、药效学和代谢 在稳定的肺和心脏/肺移植受者中。试验参与者 口服两种不同剂量的SDZ RAD(0.035和0.1% 每公斤，最高分别为2.5和7.5毫克)。有一个 两届政府之间约15天的冲销期 SDZ RAD。 这个多中心计划有二十四(24)个可评估的科目 这项研究但斯坦福大学在14名患者允许其他患者后停止了登记 中心作出贡献。在几个时间点对患者进行监测 为了安全和耐受性。每次给药后，观察一名患者的情况 现场48小时，在此期间常规执行几项测试 (生命体征、血细胞计数、生化、心电图和尿检)。然后是病人 在接下来的5天里，每天以门诊病人的身份返回。血液样本 用于SDZ RAD的药代动力学、药效学和代谢分析 和新诺拉(环孢素A，CsA)在治疗期间多次服用 头24小时及之后的每天。 本研究是SDZ RAD首次人肺给药。 移植受者。SdZ RAD是雷帕霉素的衍生物，含有 额外的2-羟乙基链。这使极性增加到 分子，使其在乙醚溶剂中比 雷帕霉素。动物研究表明，它也有类似的 免疫抑制特征和可能更好的毒理学特征 雷帕霉素在体内具有较高的口服生物利用度。在……里面 自身免疫性疾病的动物模型及同种异体移植 实验表明，SDZ RAD与CsA具有协同作用。 囊性纤维化患者(n=3)和非囊性纤维化患者(n=11)接受 尼奥拉每日两次(每日总剂量225-800毫克) 强的松为20毫克/天。患者(男6例，女8例)有躯体 体重59+-15公斤(CF)和79+-15 kg(非CF)。CMAX和AUC不同 在非CG患者中，高剂量组和低剂量组之间的比例约为3倍 2倍于CF患者。辐射吸收延迟，全身暴露 与非CF组相比，CF组降低。都是单口的 RAD剂量不影响CsA在非CF卡那的药代动力学 病人。在这项研究中，RAD耐受性良好。 SDZ RAD在稳定期肺内单次给药的初步药代动力学 没有CFs的移植受者与一篇报道的 先前对稳定肾移植受者的单次给药研究。 RAD药代动力学的进一步研究，尤其是在慢性阻塞性肺疾病患者 是有根据的。

This study of SDZ RAD was a randomized, double blind, stratified (to primary diagnosis of pancreatic insufficient cystic fibrosis and non cystic fibrosis), crossover trial designed to test the tolerability, safety, pharmacokinetics, pharmacodynamics, and metabolism of SDZ RAD in stable lung and heart/lung transplant recipients. Trial participants received two different single oral doses of SDZ RAD (0.035 and 0.1 mg/kg, up to a maximum of 2.5 and 7.5 mg respectively). There was a washout period of approximately 15 days between the two administrations of SDZ RAD. Twenty-four(24) evaluable subjects are planned for this multicenter study but Stanford stopped enrollment after 14 patients to allow other centers to contribute. Patients were monitored at several time points for safety and tolerability. After each dose a patient was observed on site for 48 hours during which several tests were routinely performed (vital signs, CBC, biochemistry, ECG, and urinalysis). Patients then returned daily as outpatients for the following 5 days. Blood samples for pharmacokinetic, pharmacodynamic, and metabolic analyses of SDZ RAD and Neoral (cyclosporine A, CsA) were taken several times during the first 24 hours and daily thereafter. This study is the first administration of SDZ RAD to human lung transplant recipients. SDZ RAD is a derivative of rapamycin bearing an additional 2-hydroxyethyl chain. This confers an increased polarity to the molecule, rendering it much more soluble in etheral solvents than rapamycin. Animal studies have shown it to have similar immunosuppressive profiles and possible a better toxicology profile than that of rapamycin in vivo, but with a greater oral bioavailability. In animal models of autoimmune disease and in allo-transplantation experiments, SDZ RAD has been shown to act in synergy with CsA. Patients with (n=3) and without (n=11) cystic fibrosis (CF) received Neoral twice daily (total daily dose of 225-800 mg) in combination with<=20mg/day of prednisone. Patients (6 males/8 females) had body weights of 59+-15kg (CF) and 79+-15 kg (Non-CF). Cmax and AUC differed 3-fold between high and low dose groups in NON-CG patients versus about 2-fold in CF patients. RAD absorption was delayed and systemic exposure reduced in the CF group compared to the Non-CF group. Both single oral doses of RAD did not affect the pharmacokinetics of CsA in Non-CF patients. RAD was well tolerated in this study. The preliminary single dose pharmacokinetics of SDZ RAD in stable lung transplant recipients without CF were similar to that reported in a previous single dose study in stable kidney transplant recipients. Further investigation of RAD pharmacokinetics especially in CF patients is warranted.