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

SDZ RAD的研究是一项随机、双盲、分层（初步诊断为胰腺不完全性囊性纤维化和非囊性纤维化）的交叉试验，旨在测试SDZ RAD在稳定的肺和心肺移植受者中的耐受性、安全性、药代动力学、药效学和代谢。试验参与者接受了两种不同的单次口服剂量的SDZ RAD（分别为0.035和0.1 mg/kg，最大剂量分别为2.5和7.5 mg）。两次给药之间约有15天的洗脱期。16名受试者在本中心完成了该方案。在几个时间点监测患者的安全性和耐受性。每次给药后，对患者进行48小时的现场观察，期间例行进行多项检查（生命体征、全血细胞计数、生化、心电图和尿液分析）。在接下来的5天里，患者每天作为门诊病人返回。在最初24小时和之后每天多次采集血液样本进行SDZ RAD和Neoral（环孢菌素a， CsA）的药代动力学、药理学和代谢分析。这项研究是第一次给药SDZ RAD人肺移植受者。SDZ RAD是雷帕霉素的衍生物，含有一个额外的2-羟乙基链。这增加了分子的极性，使其在醚溶剂中比雷帕霉素更容易溶解。动物研究表明，它具有与雷帕霉素相似的免疫抑制特征，并且可能具有更好的体内毒理学特征，但具有更高的口服生物利用度。在自身免疫性疾病的动物模型和异体移植实验中，SDZ RAD已被证明与CsA协同作用。囊性纤维化（CF）患者（n=3）和非囊性纤维化（n=11）患者接受Neoral治疗，每日2次（每日总剂量225-800 mg），联合强的松治疗<=20mg/天。患者（6男8女）体重分别为59+-15kg （CF）和79+ -15kg（非CF）。非cg患者的Cmax和AUC在高剂量组和低剂量组之间相差3倍，而CF患者相差约2倍。与非CF组相比，CF组的RAD吸收延迟，全身暴露减少。单次口服两种剂量的RAD均不影响非cf患者CsA的药代动力学。在本研究中，RAD耐受性良好。SDZ RAD在无CF的稳定肺移植受者中的初步单剂量药代动力学与之前在稳定肾移植受者中的单剂量研究相似。进一步研究RAD的药代动力学，特别是CF患者的药代动力学是有必要的。

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. 16 subjects completed this protocol at this center. 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 (cyclosporineA, 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 additional2-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 immuno- suppressive profiles and possibly 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.