Population pharmacokinetics and bioavailability of tacrolimus in kidney transplant patients
Population pharmacokinetics and bioavailability of tacrolimus in kidney transplant patients
复制标题
DOI：
10.1111/j.1365-2125.2007.02895.x
复制
发表时间：
2007-12-01
影响因子：
3.4
通讯作者：
Urien, Saik
中科院分区：
文献类型：
--
作者：
Antignac, Marie;Barrou, Benoit;Urien, Saik
目的他克莫司治疗指标较窄，患者间及患者内部差异较大，使其应用较为复杂。他克莫司群体药代动力学，包括生物利用度，在一个成人肾移植队列中进行了研究，以确定影响药代动力学的患者特征。方法纳入83例成人肾移植受者的药物监测数据，采用NONMEM方法进行人群分析。在移植后的头几个月收集数据。患者口服或静脉注射他克莫司作为三联免疫抑制方案的一部分，该方案还包括霉酚酸酯和皮质类固醇。后续剂量根据疗效和毒性的临床证据进行调整，如常规治疗药物监测。结果线性吸收消除的单室开放模型充分描述了数据。最小间隙的典型值为1.8±0.2 l h（-1）。清除率随移植后时间的增加而增加，在3.8 +/- 0.5 d后达到最大值的50%，最大值为5.6 l h（-1）。此外，如果强的松剂量为0.5 ~ 25mg，清除率增加约1.6倍（范围0.5 ~ 1.6）。分布容积的典型值V （98 +/- 13 l kg(-1)）与肾移植患者的报告值相似。他克莫司的口服生物利用度较差，为11.2 ~ 19.1%。结论术后天数和皮质类固醇剂量是影响他克莫司清除率的重要协变量。
AimThe use of tacrolimus is complicated by its narrow therapeutic index and wide intra- and interpatient variability. Tacrolimus population pharmacokinetics, including bioavailability, were investigated in an adult kidney transplant cohort to identify patient characteristics that influence pharmacokinetics.MethodsThe database (drug monitoring data) included 83 adult kidney transplant recipients and analysis was performed by a population approach with NONMEM. Data were collected during the first months after transplantation. Patients were administered oral or intravenous tacrolimus as part of a triple immunosuppressive regimen that also included mycophenolate mofetil and corticosteroids. Subsequent doses were adjusted on the basis of clinical evidence of efficacy and toxicity as in routine therapeutic drug monitoring.ResultsA one compartment open model with linear absorption and elimination adequately described the data. The typical value of minimal clearance was 1.8 +/- 0.2 l h(-1). Clearance increased with time post transplantation to reach 50% of maximal value after 3.8 +/- 0.5 days, with a maximal value of 5.6 l h(-1). Moreover clearance increased by approximately 1.6 fold (range 0.5-1.6) if the dose of prednisone was > 25 mg. The typical value for volume of distribution, V, (98 +/- 13 l kg(-1)) was similar to reported values in kidney transplant patients. The oral bioavailability of tacrolimus was poor and ranged from 11.2 to 19.1%. No covariates significantly influenced V or F.ConclusionsThe number of days postoperation and corticosteroid dose were significant covariates influencing tacrolimus clearance.