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Population Analysis of Pharmacokinetics and Pharmacodynamics of an Immunosuppresive Agent

免疫抑制剂药代动力学和药效学的群体分析

基本信息

批准号：
06672140
负责人：
YASUHARA Masato
金额：
$ 1.34万
依托单位：
Tokyo Medical and Dental University (1995)Kyoto University (1994)
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1994
资助国家：
日本
起止时间：
1994 至 1995
项目状态：
已结题

项目摘要

The establishment of reliable postoperative immunosuppressive therapy is essential to improve the outcome of organ transplantation. We have investigated the pharmacokinetics and pharmacodynamics of tacrolimus (FK506), a new immunosuppressive agent, in patients receiving living-related donor liver transplantations (LRLT) at the Second Department of Surgery, Kyoto University Hospital.1.Of the 55 patients receiving LRLT,6 had and episode of hepatic dysfunction, which was suspected to the liver allograft rejection. The onset of rejection was associated with lower blood concentration of tacrolimus. On the other hand, most of the adverse effects, such as hyperkalemia, renal dysfunction and hyperglycemia, occurred at the blood concentration higher than 20 ng/ml. Thus, the therapeutic effect and toxicity of tacrolimus were related to trough blood concentrations and the therapeutic blood concentration of tacrolimus ranged from nearly 10 to 20 ng/ml for impatients after LRLT.3.The pharmacokinetics of tacrolimus after i.v.infusion and oral administration was analyzed with an one-compartment model using the NONMEM program developed for population analysis. NONMEM analysis showed that the clearance of tacrolimus was related to body weight and days after operation and that the availability was about 19%.3.The careful dose adjustment based on TDM is essential because of the large inter-and intra-individual variability in the pharmacokinetics of tacrolimus.4.The animal experiment indicated that the clearance and hepatic extraction of tacrolimus reduced significantly in rats with hepatic dysfunction.

建立可靠的术后免疫抑制治疗是提高器官移植疗效的关键。我们研究了一种新型免疫抑制剂他克莫司（FK 506）在京都大学附属医院第二外科接受活体供肝移植（LRLT）患者中的药代动力学和药效学。排斥反应的发生与他克莫司血药浓度降低有关。另一方面，大多数不良反应，如高钾血症、肾功能不全和高血糖症，发生在血药浓度高于20 ng/ml时。因此，他克莫司的治疗效果和毒性与血药谷浓度相关，对于LRLT后的住院患者，他克莫司的治疗血药浓度范围为近10至20 ng/ml。3.静脉输注和口服给药后他克莫司的药代动力学分析使用一室模型，使用为群体分析开发的NONMEM程序。NONMEM分析显示，他克莫司的清除率与体重和术后天数有关，其利用度约为19%。3.他克莫司的药代动力学个体间和个体内变异性较大，应根据TDM进行剂量调整。