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活体供肝移植患者中他克莫司和环孢素的药效学分析

Pharmacodynamic analysis of tacrolimus and cyclosporine in living-donor liver transplant patients.

作者信息

Fukudo Masahide, Yano Ikuko, Masuda Satohiro, Fukatsu Sachio, Katsura Toshiya, Ogura Yasuhiro, Oike Fumitaka, Takada Yasutsugu, Tanaka Koichi, Inui Ken-ichi

机构信息

Department of Pharmacy, Kyoto University Hospital, Japan.

出版信息

Clin Pharmacol Ther. 2005 Aug;78(2):168-81. doi: 10.1016/j.clpt.2005.04.008.

Abstract

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 EC(50) (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.

摘要

背景

钙调神经磷酸酶抑制剂他克莫司和环孢素(国际非专利药品名称,环孢菌素)已被广泛用于预防移植后的同种异体移植物排斥反应。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相关性。

方法

40例初次接受活体供肝移植的患者参与了本研究,其中30例接受他克莫司治疗,10例接受环孢素治疗。在术后的前14天内,我们同时测定了外周血单个核细胞中的血药浓度和钙调神经磷酸酶活性。还检查了肾毒性和急性排斥反应与血药浓度和钙调神经磷酸酶活性的关系。

结果

他克莫司浓度大于20 ng/mL时仅部分抑制钙调神经磷酸酶活性,而环孢素浓度大于700 ng/mL时几乎可完全抑制该活性。根据最大效应模型,他克莫司和环孢素的半数最大效应浓度(EC50)的群体均值估计分别为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)。与无此不良事件的患者相比,两组中发生肾毒性的患者谷浓度显著更高。此外,他克莫司组发生急性排斥反应的患者谷浓度显著更低,钙调神经磷酸酶活性更高。

结论

在活体供肝移植患者中,他克莫司和环孢素对外周血单个核细胞中钙调神经磷酸酶活性的抑制作用不同。结合血药浓度监测进行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。

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