Population pharmacokinetics of sirolimus in kidney transplant patients
Population pharmacokinetics of sirolimus in kidney transplant patients
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DOI：
10.1016/s0009-9236(97)90192-2
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发表时间：
1997-04-01
影响因子：
6.7
通讯作者：
Jusko, WJ
中科院分区：
文献类型：
--
作者：
Ferron, GM;Mishina, EV;Jusko, WJ
目的：采用两阶段非线性混合效应模型群体方法，研究免疫抑制剂西罗莫司（原雷帕霉素）在肾移植患者体内的剂量相关药代动力学。方法：来自三个中心（德国、英国和瑞典）接受稳态口服剂量环孢素（环孢素）的患者（n = 36）在单次口服剂量为3,5,10和15mg /m的西罗莫司(2)后进行评估。血浆和全血西罗莫司样品采用高效液相色谱/质谱联用方法进行分析，同时采用具有截距/斜率或间隙/体积项的双指数函数进行拟合，以及一阶吸收（k(a)）和滞后时间。结果:非线性混合效应模型方法（P-Pharm）可以更好地表征西罗莫司的动力学，特别是在每个患者可获得的数据较少的吸收和分布阶段，西罗莫司在全血和血浆之间的分布与浓度无关，平均血/血浆比（变异系数）为30.9(48.5%)，消除不受剂量的影响。西罗莫司的终末半衰期为63小时（27.5%），口服血液表观清除率为8.9 L/hr(38.2%)，西罗莫司的分布参数受体重和表面积的影响。西罗莫司吸收迅速，吸收滞后时间为0.27小时（35.1%），k(a)为2.77小时（-1）（48.4%），西罗莫司与环孢素同时给药未发现药代动力学相互作用。结论：本报告提供了西罗莫司在同时接受环孢素治疗的肾移植受者中的初始群体药代动力学，西罗莫司的血液和血浆药代动力学在剂量3 ~ 15mg /m范围内呈双指数和线性(2)，西罗莫司与环孢素之间未发现药代动力学相互作用。
Objective: 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.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/m(2). 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 (k(a)) and a lag-time.Results: 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 k(a) of 2.77 hr(-1) (48.4%), The concomitant administration of sirolimus and cyclosporine did not reveal any pharmacokinetic interactions.Conclusion: 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/m(2), No pharmacokinetic interaction was found between sirolimus and cyclosporine.