Pharmacokinetics of an everolimus-cyclosporine immunosuppressive regimen over the first 6 months after kidney transplantation
Pharmacokinetics of an everolimus-cyclosporine immunosuppressive regimen over the first 6 months after kidney transplantation
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DOI：
10.1034/j.1600-6143.2003.00107.x
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发表时间：
2003-05-01
影响因子：
8.8
通讯作者：
Rordorf, C
中科院分区：
文献类型：
--
作者：
Kovarik, JM;Kaplan, B;Rordorf, C
在731例接受0.75或1.5 mg bid依维莫司加环孢菌素和皮质类固醇的患者中，对移植后前6个月内依维莫司的药代动力学进行了表征。药代动力学数据包括在所有患者中获得的4014个依维莫司谷浓度（Cmin）和在261名患者的子集中在第2、3和6个月获得的659个浓度-时间曲线下面积（AUC）曲线。在0.75和1.5 mg bid剂量下，Cmins平均值为4.3+/-2.4和7.2+/-4.2 ng/mL，表明在较高剂量水平下比例不足20%。与第2个月至第6个月的值相比，第1个月的Cmin值低19-34%。AUC与剂量成比例且随时间稳定，两个剂量水平的平均值分别为77+/-32和136+/-57 ng.h.mL（-1）。AUC的患者内和患者间变异性分别为27%和31%。性别、年龄（16- 66岁）或体重（42- 132 kg）对AUC无影响。依维莫司暴露在黑人中平均显著降低20%。依维莫司暴露在移植后前6个月内相对稳定，在治疗剂量范围内与剂量比例性无重大偏离。体重调整剂量（mg/kg）似乎没有必要。与白色患者相比，黑人患者对依维莫司的生物利用度可能较低和/或清除率较高。
The pharmacokinetics of everolimus were characterized over the first 6 months post transplant in 731 patients receiving either 0.75 or 1.5 mg bid everolimus in addition to cyclosporine and corticosteroids. Pharmacokinetic data consisted of 4014 everolimus trough concentrations (Cmin) obtained in all patients and 659 area under the concentration-time curve (AUC) -profiles obtained at months 2, 3, and 6 in a subset of 261 patients. Cmins averaged 4.3+/-2.4 and 7.2+/-4.2 ng/mL at 0.75 and 1.5mg bid, indicating a 20% under-proportionality at the upper dose level. Cmins were 19-34% lower in the first month compared with months 2 through 6-values. AUC was dose-proportional and stable over time, averaging 77+/-32 and 136+/-57 ng.h.mL(-1) at the two dose levels. Within- and between-patient variability in AUC were 27% and 31%, respectively. There was no influence of sex, age (16-66years), or weight (42-132kg) on AUC. Everolimus exposure was significantly lower by an average 20% in blacks. Everolimus exposure was relatively stable over the first 6 months post transplant, with no major departure from dose-proportionality over the therapeutic dose range. Weight-adjusted dosing (mg/kg) does not appear warranted. Black patients may have lower bioavailability and/or higher clearance of everolimus compared with white patients.