A Clinical Pharmacokinetic Study of Tacrolimus and Sirolimus Combination Immunosuppression Comparing Simultaneous to Separated Administration
A Clinical Pharmacokinetic Study of Tacrolimus and Sirolimus Combination Immunosuppression Comparing Simultaneous to Separated Administration
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他克莫司和西罗莫司联合免疫抑制同时与分开给药的临床药代动力学研究
DOI：
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发表时间：
2002
影响因子：
2.5
通讯作者：
A. Macdonald
中科院分区：
文献类型：
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作者：
Vivian Charles McAlister;K. Mahalati;K. Peltekian;A. Fraser;A. Macdonald
他克莫司（TAC）和西罗莫司（SRL）之间的药代动力学（PK）相互作用，类似结构的免疫抑制化合物，共享结合蛋白，是未知的。SRL与环孢菌素（CsA）的组合进行了研究，并建议两种药物给药之间的4小时间隔，即使这对患者来说是不方便的，可能会影响依从性。25例接受SRL和低剂量TAC联合治疗的肝脏和肾脏-胰腺移植受者完成了完整的PK研究，同时接受4小时间隔给药（ID），然后同时给药。采集全血用于TAC和SRL水平的免疫测定。SRL和TAC的血药浓度/剂量比在患者之间的差异分别为8倍和5倍，但谷浓度水平（C 0）和药物暴露浓度-时间曲线下面积（AUC）之间的相关性极佳（TAC：r2 = 0.82; SRL：r2 = 0.83）。SRL和TAC的PK特征均未因同时给药而改变。TAC的剂量校正AUC和C 0与SRL相关（r2分别= 0.8和0.8）。当TAC和SRL联合使用时，骨髓抑制和肾毒性没有增强，也没有观察到任何新的毒性。这些数据证实，移植后同时给予TAC和SRL是安全的，谷水平监测足以控制治疗。
The pharmacokinetic (PK) interaction between tacrolimus (TAC) and sirolimus (SRL), similarly structured immunosuppressive compounds that share binding proteins, is unknown. The combination of SRL with cyclosporin (CsA) has been studied, and a 4-hour interval between dosing of the two drugs is recommended even though it is inconvenient for patients and may affect compliance. Twenty-five liver and kidney–pancreas transplant recipients treated with a combination of SRL and low-dose TAC completed full PK studies while being treated with 4-hour interval dosing (ID) and then with simultaneous dosing. Whole blood was sampled for immunoassay measurement of TAC and SRL levels. Blood concentration/dose ratios of SRL and TAC varied between patients by a factor of 8 and 5, respectively, but correlation between trough concentration levels (C0) and drug exposure area under the concentration–time curve (AUC) was excellent (TAC: r2 = 0.82; SRL: r2 = 0.83). Neither PK profiles of SRL nor those of TAC were altered by simultaneous administration. Dose-corrected AUC and C0 of TAC correlated with SRL (r2 = 0.8 and 0.8, respectively). Bone marrow suppression and nephrotoxicity were not enhanced nor were any new toxicities observed when TAC and SRL were used in combination. These data confirm that simultaneous dosing of TAC and SRL after transplantation is safe and that trough level monitoring is adequate to control therapy.