Population Analysis of Pharmacokinetics and Pharmacodynamics of an Immunosuppresive Agent

建立可靠的术后免疫抑制治疗对改善器官移植的预后至关重要。我们研究了一种新的免疫抑制剂他克莫司（FK506）在京都大学医院第二外科活体肝移植（LRLT）患者中的药代动力学和药效学。55例接受LRLT的患者中，有6例出现肝功能障碍，怀疑与肝移植排斥反应有关。排斥反应的发生与他克莫司血药浓度降低有关。另一方面，高钾血症、肾功能障碍、高血糖等不良反应大多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低血药浓度有关，他克莫司在lrlt后的治疗血药浓度在近10 ~ 20 ng/ml之间。他克莫司经静脉滴注和口服给药后的药代动力学采用单室模型，采用用于人群分析的NONMEM程序进行分析。NONMEM分析显示，他克莫司的清除率与体重和术后天数有关，可得性约为19%。由于他克莫司的药代动力学存在很大的个体间和个体内差异，因此根据TDM仔细调整剂量是必要的。动物实验表明，肝功能障碍大鼠对他克莫司的清除和肝提取明显降低。

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.