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: 6219377
• 负责人: RANDALL E MORRIS
• 金额: $ 0.06万
• 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/6219377
• 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. 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.

本SDZ RAD研究是一项随机、双盲、分层（主要诊断为胰腺囊性纤维化不足和非囊性纤维化）、交叉试验，旨在检测SDZ RAD在稳定肺和心/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SDZ RAD单次口服剂量（0.035和0.1 mg/kg，最大剂量分别为2.5和7.5 mg）。SDZ RAD两次给药之间约有15天的洗脱期。16例受试者在该中心完成了本方案。在几个时间点监测患者的安全性和耐受性。每次给药后，在研究中心观察患者48小时，在此期间常规进行几项检查（生命体征、CBC、生化、ECG和尿分析）。然后患者在接下来的5天内每天作为门诊患者返回。在前24小时内多次采集用于SDZ RAD和Neoral（环孢素A，CsA）药代动力学、药效学和代谢分析的血样，此后每天采集一次。本研究是SDZ RAD首次用于人类肺移植受者。SDZ RAD是雷帕霉素的衍生物，带有额外的2-羟乙基链。这赋予了分子增加的极性，使其在醚溶剂中比雷帕霉素更易溶。动物研究表明，它具有类似的免疫抑制特性，可能比体内雷帕霉素具有更好的毒理学特性，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同种异体移植实验中，SDZ RAD已被证明与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Neoral每日两次（每日总剂量为225-800 mg）联合泼尼松<= 20 mg/天。患者（6名男性/8名女性）的体重为59 ± 15 kg（CF）和79 ± 15 kg（非CF）。在非CG患者中，高剂量组和低剂量组之间的Cmax和AUC相差3倍，而在CF患者中相差约2倍。与非CF组相比，CF组的RAD吸收延迟，全身暴露减少。RAD的两种单次口服剂量不影响非CF患者中CsA的药代动力学。RAD在本研究中耐受性良好。在无CF的稳定肺移植受者中，SDZ RAD的初步单次给药药代动力学与先前在稳定肾移植受者中进行的单次给药研究中报告的结果相似。需要进一步研究RAD的药代动力学，尤其是在CF患者中。