Fukatsu S, Yano I, Igarashi T, Hashida T, Takayanagi K, Saito H, Uemoto S, Kiuchi T, Tanaka K, Inui K, Tanaka K, Inui K
Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Japan.
Eur J Clin Pharmacol. 2001 Sep;57(6-7):479-84. doi: 10.1007/s002280100331.
To characterize the pharmacokinetics of tacrolimus in adult recipients receiving living-donor liver transplantation (LDLT).
Thirty-five patients were given tacrolimus as 18- to 60-h intravenous infusions after surgery, followed by a 4-week course of oral dose therapy (at 0900 hours and 2100 hours). Blood samples were collected daily in the morning (0800 hours) beginning the day after surgery. Whole blood concentration data were evaluated by nonlinear mixed-effect modeling using the program NONMEM and were characterized using a one-compartment model.
The clearance (CL, l h(-1)) was related to the grafted hepatic weight, postoperative days (POD), and hepatic and renal dysfunction. Interindividual variabilities in CL, volume of distribution (V), and bioavailability (F) were 57.4%. 39.7%, and 63.0%, respectively, and the correlation between individual CL and F was 0.776. Residual intraindividual variability was 2.9 ng ml(-1). Based on the estimated final parameters, a typical recipient of LDLT with grafted hepatic weight of 600 g and normal hepatic and renal function would have a CL of 0.737 l h(-1) on POD 0 and 1.14 l h(-1) on POD 30, V of 1.52 l kg(-1) and F of 6.8%.
Nonlinear mixed-effect modeling was useful for analysis of pharmacokinetic characteristics of tacrolimus in LDLT patients. Immediately after surgery, patients receiving LDLT showed a smaller CL value than other transplant patients, and CL value increased with POD within 30 days after surgery. The estimated population pharmacokinetic parameters can be applied for a priori dosage calculations in adult patients with LDLT.
描述他克莫司在接受活体供肝肝移植（LDLT）的成年受者体内的药代动力学特征。
35例患者术后接受18至60小时的他克莫司静脉输注，随后进行为期4周的口服给药治疗（每天09:00和21:00）。术后次日起每天上午（08:00）采集血样。使用NONMEM程序通过非线性混合效应模型评估全血浓度数据，并采用单室模型进行特征描述。
清除率（CL，l h⁻¹）与移植肝脏重量、术后天数（POD）以及肝肾功能障碍有关。CL、分布容积（V）和生物利用度（F）的个体间变异分别为57.4%、39.7%和63.0%，个体CL与F之间的相关性为0.776。个体内残余变异为2.9 ng ml⁻¹。根据估计的最终参数，移植肝脏重量为600 g且肝肾功能正常的典型LDLT受者在POD 0时的CL为0.737 l h⁻¹，在POD 30时为1.14 l h⁻¹，V为1.52 l kg⁻¹，F为6.8%。
非线性混合效应模型有助于分析LDLT患者他克莫司的药代动力学特征。术后即刻，接受LDLT的患者CL值低于其他移植患者，且术后30天内CL值随POD增加。估计的群体药代动力学参数可用于LDLT成年患者的先验剂量计算。
