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

比较 SDZ RAD 在心/肺移植中的安全性的两种剂量研究

• 批准号: 6115068
• 负责人: RANDALL E MORRIS
• 金额: $ 4.03万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-01 至 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6115068
• 关键词: body weight; clinical research; clinical trials; cystic fibrosis; dosage; drug administration rate /duration; drug metabolism; drug screening /evaluation; endocrine disorder chemotherapy; heart transplantation; human subject; human therapy evaluation; immunosuppressive; lung transplantation; oral administration; pharmacokinetics; sirolimus; transplant rejection

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.

SDZ RAD的这项研究是一项随机、双盲、分层（至 初步诊断胰腺囊性纤维化不足， 囊性纤维化），设计用于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 稳定的肺和心脏/肺移植受者。试验参与者 接受了两种不同的单剂量SDZ RAD（0.035和0.1 mg/kg，最高分别为2.5和7.5 mg）。有一个 两次给药之间的洗脱期约为15天 SDZ RAD 本多中心计划纳入24例可评价受试者 研究，但斯坦福大学停止招募后，14名患者，让其他 中心做贡献。在几个时间点对患者进行监测 安全性和耐受性。每次给药后，观察患者 研究中心48小时，在此期间进行了几项常规检测 （生命体征、CBC、生化、ECG和尿分析）。然后患者 在接下来的5天里，每天作为门诊病人返回。血样 SDZ RAD的药代动力学、药效学和代谢分析 和Neoral（环孢素A，CsA）在治疗期间服用了几次。 前24小时及其后每天。 本研究是首次将SDZ RAD应用于人肺 移植接受者SDZ RAD是雷帕霉素的衍生物， 额外的2-羟乙基链。这赋予了增加的极性， 分子，使其更容易溶于醚溶剂比 雷帕霉素动物研究表明， 免疫抑制特性和可能更好的毒理学特性， 雷帕霉素在体内，但具有更大的口服生物利用度。在 自身免疫性疾病和同种异体移植中的动物模型 在实验中，SDZ RAD已显示与CsA协同作用。 患有（n=3）和不患有（n=11）囊性纤维化（CF）的患者接受了 新口服每日两次（每日总剂量为225-800 mg）联合用药 泼尼松<= 20 mg/天。患者（6例男性/8例女性）有身体 体重为59+-15 kg（CF）和79+-15 kg（非CF）。Cmax和AUC不同 3-NON-CG患者中高剂量组和低剂量组之间的倍数， 2-CF患者中的倍数。RAD吸收延迟，全身暴露 与非CF组相比，CF组中的降低。均为单次经口 RAD的剂量不影响CsA在非CF中的药代动力学 患者RAD在本研究中耐受性良好。 SDZ RAD单次给药在稳定肺内的初步药代动力学 没有CF的移植受者与一项研究中报道的相似。 既往在稳定肾移植受者中进行的单次给药研究。 RAD药代动力学的进一步研究，尤其是在CF患者中 是有根据的