他克莫司在心脏移植患者体内的临床药动学

Clinical pharmacokinetics of Tacrolimus in heart transplantation recipients

目的 :了解他克莫司在心脏移植患者体内的药代动力学特征 ,为患者实施用药的个体化。方法 :采集 4例心脏移植患者稳态时一个用药间隔 (τ)内 9个不同时间点血样 ,以微粒子酶标免疫分析法 (MEIA)测定全血中他克莫司的浓度 ,计算他克莫司在个体患者体内的药动学参数 ,并以此参数为依据实施用药的个体化。以他克莫司谷浓度结合患者临床疗效及不良反应的情况 ,总结他克莫司在心脏移植术后的治疗窗。结果 :患者口服他克莫司 (4～ 5mg/ 8h)后 ,其体内处置为一室开放模型 ,平均药动学参数 Tm ax,Cmax,T1 /2 ke和 AUC依次分别为 1.2± 0 .4h,2 9± 7m g· L- 1 ,7.6± 1.2 h和 2 75± 10 8mg· h- 1 · L- 1 。术后 1年来他克莫司谷浓度控制在 2 5～ 5 m g· L- 1 ,患者未出现严重的排斥或中毒反应。结论 :他克莫司药动学的个体差异较大 ,应加强全血谷浓度监测 ,确保用药的安全有效。他克莫司在心脏移植的治疗窗 (谷浓度 )为 :0～ 1个月 15～ 2 0 mg· L- 1 ,1～ 3个月 10～ 15 mg· L- 1 ,3～ 6个月8～ 12 m g· L- 1 ,6个月后 5～ 8mg· L- 1 ,此浓度范围即可有满意的免疫抑制效果 ,又可减少他克莫司不良反应。

AIM:To investigate the clinical pharmacokinetics of tacrolimus in heart transplantation recipients and to provide gist for clinical individual dosage. METHODS:When level of tacrolimus was in a steady state, the whole blood samples of the 4 heart transplant recipients were collected for 9 times in scheduled time during a τ. The whole blood concentrations of tacrolimus were analyzed by microparticle enzyme immunoassay (MEIA) before and after the administration of the medicine, the concentration-time data was fitted with the computer software package PKBP-N1, and the parameters of pharmacokinetics were calculated. The patients were given individual medication of tacrolimus according to the parameters of pharmacokinetics. The treatment window of tacrolimus was concluded by clinical curative effect and adverse drug reaction (ADR) of the patients. RESULTS: Compartmental analysis yielded a one-compartment open model in the steady state after oral administration of tacrolimus 4～5 mg/8 h. The mean pharmacokinetics parameters of tacrolimus were as follows: the Tmax = 1.2±0.4 h ,Cmax = 29±7 mg·L -1 , t 1/2 Ke = 7.6±1.2 h, AUC=275±108 mg·h -1 ·L -1 , respectively. The heart rejection and ADR of tacrolimus did not occur in 1 year after the operation when tacrolimus whole blood trough concentration was 25～5 mg·L -1 . CONCLUSION: The pharmacokinetics of tacrolimus was highly variable among patients. The whole blood trough concentration of tacrolimus should be monitored to ensure safety and efficacy. The range of therapeutic window trough levels of tacrolimus was 15～20 mg·L -1 within the first month, 10～15 mg·L -1 within the second and third months,8～12 mg·L -1 within the fourth to sixth months,5～8 mg·L -1 from the seventh month after the transplantation. This range of therapeutic window of tacrolimus was ideal for heart transplant recipients with less rejection and ADR.