Kinetics and dynamics of single oral doses of sirolimus in sixteen renal transplant recipients
Kinetics and dynamics of single oral doses of sirolimus in sixteen renal transplant recipients
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DOI：
10.1097/00007691-199708000-00007
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发表时间：
1997-08-01
影响因子：
2.5
通讯作者：
Groth, CG
中科院分区：
文献类型：
--
作者：
Brattstrom, C;Sawe, J;Groth, CG
西罗莫司是一种新的免疫抑制药物，已在动物实验中进行了评估。目前的研究是在人体中进行的，西罗莫司的剂量从3 mg/m2到15 mg/m2。本I期研究纳入了16名肾移植受者，以确定西罗莫司口服单次剂量递增的安全性、耐受性和初步药代动力学。所有16例患者在研究前至少6个月接受肾移植后移植肾功能稳定。基础免疫抑制剂包括环孢素和泼尼松龙（n = 10）或环孢素，硫唑嘌呤和泼尼松龙（n = 6）。4组（1，3 mg/m（2）; IL，5 mg/m（2）; III，10 mg/m（2）; IV，15 mg/m（2））的4名患者被随机分配接受西罗莫司（n = 3）或安慰剂（n = 1）。在接受西罗莫司治疗的12例患者中，5例发生轻度一过性研究事件，如头痛、恶心、轻度头晕、低血糖、鼻衄和血小板减少。未发生严重不良事件，且无与西罗莫司单次给药相关的肾毒性作用。唯一被判定为很可能与西罗莫司相关的研究事件是一例血小板减少症。其他事件被评价为可能相关。血小板减少发生在最高剂量水平（15 mg/m2西罗莫司）。在安慰剂组的两名患者中，观察到肝酶和血清淀粉酶轻微升高。通过电喷雾-高效液相/质谱分光光度法（ESP-HPLC/MS）分析血液和血浆西罗莫司浓度。西罗莫司显示出广泛的红细胞分布，平均血液/血浆比为49.1。消除半衰期范围为43.8 - 86.5小时（平均56.9小时）。C-max和浓度-时间曲线下面积（AUC）与3 - 15 mg/m2剂量之间存在合理相关性（2）。经口给药清除率范围为42 - 339 ml/h.kg。西罗莫司给药前后，环孢素谷浓度或AUC无临床显著差异。稳定的肾移植受者单次口服西罗莫司3 - 15 mg/m2是安全的，耐受性良好。血小板减少可能是剂量限制性毒性。其他II期和III期临床试验将确定西罗莫司的免疫抑制疗效。
Sirolimus is a new immunosuppressive drug that has been evaluated in animal experiments. The current study was conducted on humans with reformulated sirolimus in doses from 3 mg/m(2) to 15 mg/m(2). Sixteen renal transplant recipients were included in this phase I study to determine the safety, tolerance, and preliminary pharmacokinetics of increasing single doses of orally administered sirolimus. All 16 patients had stable renal graft function after a renal transplant at least 6 months before the study. Basal immunosuppression consisted of cyclosporine and prednisolone (n = 10) or cyclosporine, azathioprine, and prednisolone (n = 6). Four groups (1, 3 mg/m(2); IL, 5 mg/m(2); III, 10 mg/m(2); IV, 15 mg/m(2)) of four patients were assigned randomly to receive sirolimus (n = 3) or placebo (n = 1). Among the 12 patients who received sirolimus, five had mild transient study events such as headache, nausea, mild dizziness, hypoglycemia, epistaxis, and decrease in platelets. No serious adverse events occurred and no nephrotoxic effects could be related to the single dose administration of sirolimus. The only study event that was judged as probably related to sirolimus was the single case of thrombocytopenia. The other events were evaluated as possibly related. Thrombocytopenia occurred at the highest dose level (15 mg/m(2) sirolimus). In two of the patients in the placebo group, slight elevations of liver enzymes and serum amylase were seen. Blood and plasma sirolimus concentrations were analyzed by an electrospray-high performance liquid/mass spectrophotometric (ESP-HPLC/MS) method Sirolimus showed an extensive red blood cell distribution with a mean blood/plasma ratio of 49.1. The elimination half-life ranged from 43.8 to 86.5 hours (mean 56.9 hours). The C-max and the area under the concentration versus time curves (AUC) correlated reasonably with doses from 3 to 15 mg/m(2). The oral dose clearance ranged from 42 to 339 ml/h.kg. No clinically significant differences were seen in the trough concentrations of cyclosporine or the AUCs before and after the administration of sirolimus. Administration of single oral doses of sirolimus from 3 to 15 mg/m(2) was safe and well tolerated in stable renal transplant recipients. Thrombocytopenia may be the dose-limiting toxicity. Additional phase II and phase III clinical trials will define the immunosuppressive efficacy of sirolimus.