Pharmacodynamic analysis of tacrolimus and cyclosporine in living-donor liver transplant patients
Pharmacodynamic analysis of tacrolimus and cyclosporine in living-donor liver transplant patients
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DOI：
10.1016/j.clpt.2005.04.008
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发表时间：
2005-08-01
影响因子：
6.7
通讯作者：
Inui, K
中科院分区：
文献类型：
--
作者：
Fukudo, M;Yano, I;Inui, K
背景资料：钙调磷酸酶抑制剂他克莫司和环孢素（INN，环孢素）已被广泛用于预防移植后的同种异体排斥反应。我们研究了这两种药物的药效学特性及其在肝移植中的临床意义。研究方法：40例初治活体肝移植患者参加了这项研究，他们接受了他克莫司（N = 30）或环孢素（N = 10）治疗。我们同时测定了血液药物浓度和钙调磷酸酶活性在外周血单核细胞在术后的第一个14天。肾毒性和急性排斥反应也检查了血药浓度和钙调神经磷酸酶activity.Results：钙调神经磷酸酶活性只有部分抑制他克莫司浓度大于20 ng/ mL，虽然它可以几乎完全抑制环孢素浓度大于700 ng/mL。根据最大效应模型，他克莫司和环孢素的EC 50（产生半数最大效应的血药浓度）的群体平均估计值分别为26.4 ng/mL（95%置信区间[CI]，15.7-37.1 ng/mL）和200 ng/mL（95% CI，127-274 ng/mL）。两组中发生肾毒性的患者的谷浓度均显著高于未发生该不良事件的患者。此外，在他克莫司组急性排斥反应的患者有显着降低谷浓度和较高的钙调神经磷酸酶活性比那些没有排斥epission.Conclusions：他克莫司和环孢素对钙调神经磷酸酶活性的抑制作用不同的外周血单核细胞在活体肝移植患者。结合血药浓度监测的药效学评估可能有助于确定他克莫司和环孢素的个体治疗范围。
Background: The calcineurin inhibitors tacrolimus and cyclosporine (INN, ciclosporin) have been widely used to prevent allograft rejection after transplantation. We investigated pharmacodynamic properties of the 2 drugs and their clinical relevance in liver transplantation. Methods: Forty de novo living-donor liver transplant patients participated in this study, and they were treated with either tacrolimus (N = 30) or cyclosporine (N = 10). We simultaneously measured blood drug concentrations and calcineurin phosphatase activity in peripheral blood mononuclear cells during the first 14 postoperative days. Nephrotoxicity and acute rejection were also examined in relation to the blood drug concentrations and calcineurin activity.Results: Calcineurin activity was only partially inhibited by tacrolimus concentrations greater than 20 ng/ mL, although it could be almost completely inhibited by cyclosporine concentrations greater than 700 ng/mL. According to a maximum effect model, the population mean estimates of the EC50 (blood concentration that yields a half-maximal effect) for tacrolimus and cyclosporine were 26.4 ng/mL (95% confidence interval [CI], 15.7-37.1 ng/mL) and 200 ng/mL (95% CI, 127-274 ng/mL), respectively. Patients with nephrotoxicity in both groups had significantly higher trough concentrations compared with those without this adverse event. In addition, patients with acute rejection in the tacrolimus group had significantly lower trough concentrations and higher calcineurin activity than those without a rejection episode.Conclusions: The inhibitory effects on calcineurin activity in peripheral blood mononuclear cells differed between tacrolimus and cyclosporine in living-donor liver transplant patients. Pharmacodynamic assessment in combination with blood concentration monitoring may be useful for determining the individual therapeutic range of tacrolimus and cyclosporine.