Ferron G M, Mishina E V, Zimmerman J J, Jusko W J
Department of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo, USA.
Clin Pharmacol Ther. 1997 Apr;61(4):416-28. doi: 10.1016/S0009-9236(97)90192-2.
To characterize the dose-related pharmacokinetics of the immunosuppressant agent sirolimus (formerly rapamycin) in kidney transplant patients by use of two-stage and nonlinear mixed-effect model population methods.
Patients (n = 36) from three centers (Germany, the United Kingdom, and Sweden) who received steady-state oral doses of cyclosporine (ciclosporin) were assessed after single oral administration of sirolimus at doses of 3, 5, 10, and 15 mg/m2. Plasma and whole blood sirolimus samples were analyzed by a high-performance liquid chromatographic/mass spectrophotometric method. Simultaneous fitting used biexponential functions with intercept/slope or clearance/volume terms, as well as first-order absorption (ka) and a lag-time.
The nonlinear mixed-effect model method (P-Pharm) provided a better characterization of sirolimus kinetics, especially for the absorption and distribution phases where fewer data were available per patient. Sirolimus distribution between whole blood and plasma was concentration-independent, with a mean blood/plasma ratio (coefficient of variation) of 30.9 (48.5%). Elimination was not influenced by dose, as shown by estimates of the terminal half-life of 63 hours (27.5%) and apparent oral blood clearance of 8.9 L/hr (38.2%). Sirolimus distribution parameters were influenced by body weight and surface area. Sirolimus was rapidly absorbed, as shown by the absorption lag-time of 0.27 hour (35.1%), and ka of 2.77 hr-1 (48.4%). The concomitant administration of sirolimus and cyclosporine did not reveal any pharmacokinetic interactions.
This report provides an initial population pharmacokinetics of sirolimus in kidney transplant recipients receiving cyclosporine concurrently. Sirolimus blood and plasma pharmacokinetics were biexponential and linear for doses from 3 to 15 mg/m2. No pharmacokinetic interaction was found between sirolimus and cyclosporine.
采用两阶段和非线性混合效应模型群体方法，描述免疫抑制剂西罗莫司（原名雷帕霉素）在肾移植患者中的剂量相关药代动力学特征。
来自三个中心（德国、英国和瑞典）的36例接受稳态口服环孢素的患者，在单次口服3、5、10和15mg/m²剂量的西罗莫司后进行评估。采用高效液相色谱/质谱法分析血浆和全血中西罗莫司样本。同时拟合使用具有截距/斜率或清除率/体积项的双指数函数，以及一级吸收（ka）和滞后时间。
非线性混合效应模型方法（P-Pharm）能更好地描述西罗莫司的动力学特征，特别是在吸收和分布阶段，每位患者的数据较少。西罗莫司在全血和血浆之间的分布与浓度无关，平均血/浆比（变异系数）为30.9（48.5%）。如终末半衰期估计值为63小时（27.5%）和表观口服血清除率为8.9L/小时（38.2%）所示，消除不受剂量影响。西罗莫司的分布参数受体重和体表面积影响。西罗莫司吸收迅速，吸收滞后时间为0.27小时（35.1%），ka为2.77小时⁻¹（48.4%）。西罗莫司与环孢素的联合给药未显示出任何药代动力学相互作用。
本报告提供了同时接受环孢素的肾移植受者中西罗莫司的初始群体药代动力学。西罗莫司的血药和血浆药代动力学在3至15mg/m²剂量范围内呈双指数和线性。未发现西罗莫司与环孢素之间存在药代动力学相互作用。
