Antignac Marie, Barrou Benoit, Farinotti Robert, Lechat Philippe, Urien Saïk
Pharmacy Department, Pitié Salpêtrière Hospital, AP HP-47 Bd de l'hôpital, 75013 Paris, France.
Br J Clin Pharmacol. 2007 Dec;64(6):750-7. doi: 10.1111/j.1365-2125.2007.02895.x. Epub 2007 Apr 10.
The 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.
The 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.
A 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.
The number of days postoperation and corticosteroid dose were significant covariates influencing tacrolimus clearance.
他克莫司的使用因治疗指数窄以及患者内和患者间差异大而变得复杂。在一个成人肾移植队列中研究了他克莫司的群体药代动力学，包括生物利用度，以确定影响药代动力学的患者特征。
数据库（药物监测数据）包括83名成人肾移植受者，并采用NONMEM群体方法进行分析。数据在移植后的头几个月收集。患者接受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，如同常规治疗药物监测一样。
一个具有线性吸收和消除的一室开放模型充分描述了数据。最小清除率的典型值为1.8±0.2 l h⁻¹。清除率在移植后随时间增加，在3.8±0.5天后达到最大值的50%，最大值为5.6 l h⁻¹。此外，如果泼尼松剂量>25 mg，清除率增加约1.6倍（范围0.5 - 1.6）。分布容积V的典型值（98±13 l kg⁻¹）与肾移植患者的报道值相似。他克莫司的口服生物利用度较差，范围为11.2%至19.1%。没有协变量对V或F有显著影响。
术后天数和皮质类固醇剂量是影响他克莫司清除率的显著协变量。
