College of Pharmacy, Seoul National University, Seoul, Korea.
Ann Pharmacother. 2012 Sep;46(9):1141-51. doi: 10.1345/aph.1R004. Epub 2012 Sep 4.
Cyclosporine is often used to prevent allograft rejection in renal transplant recipients. However, cyclosporine has a narrow therapeutic window and large variability in its pharmacokinetics. Individual characteristics and genetic polymorphisms can cause the variation. Hence, it is important to determine the cause(s) of the variation in cyclosporine pharmacokinetics. To our knowledge, this is the first reported population pharmacokinetic study of cyclosporine in living donor renal transplant recipients that considered the genetic polymorphism as a covariate.
To build a population pharmacokinetic model of cyclosporine in living donor renal transplant recipients and identify covariates including CYP3A5*3, ABCB1 genetic polymorphisms that affect cyclosporine pharmacokinetic parameters.
Clinical characteristics and cyclosporine concentration data for 69 patients who received cyclosporine-based immunosuppressive therapy after living donor renal transplantation were collected retrospectively for up to 400 postoperative days. CYP3A5*1/*3 and ABCB1C1236T, G2677T/A, C3435T geno-typing was performed. A population pharmacokinetic analysis was conducted using a NONMEM program. After building the final model, 1000 bootstrappings were performed to validate the final model.
In total, 2034 blood samples were collected. A 1-compartment open model with first-order absorption and elimination was chosen to describe the pharmacokinetics of cyclosporine. A population pharmacokinetic analysis showed that postoperative days, sex, and CYP3A5 genotype significantly affected the pharmacokinetics of cyclosporine. The final estimate of mean clearance was 56 L/h, and the mean volume of distribution was 4650 L. The interindividual variability for these parameters was 22.98% and 51.48%, respectively.
Using the present model to calculate the dose of cyclosporine with CYP3A5 genotyping can be possible for the patients whose cyclosporine concentration is not within the therapeutic range even with therapeutic drug monitoring.
环孢素常用于预防肾移植受者的同种异体移植排斥反应。然而，环孢素的治疗窗较窄，其药代动力学的变异性较大。个体特征和遗传多态性可能导致这种变异。因此，确定环孢素药代动力学变异的原因很重要。据我们所知，这是首例考虑遗传多态性作为协变量的活体供肾肾移植受者环孢素群体药代动力学研究。
建立活体供肾肾移植受者环孢素的群体药代动力学模型，并确定包括 CYP3A5*3、ABCB1 遗传多态性在内的影响环孢素药代动力学参数的协变量。
回顾性收集 69 例接受环孢素为基础的免疫抑制治疗的活体供肾肾移植受者的临床特征和环孢素浓度数据，最长达 400 个术后天。进行 CYP3A5*1/*3 和 ABCB1C1236T、G2677T/A、C3435T 基因分型。使用 NONMEM 程序进行群体药代动力学分析。建立最终模型后，进行了 1000 次自举验证以验证最终模型。
共采集 2034 个血样。选择 1 室开放模型，采用一级吸收和消除来描述环孢素的药代动力学。群体药代动力学分析表明，术后天数、性别和 CYP3A5 基因型显著影响环孢素的药代动力学。最终估计的平均清除率为 56 L/h，平均分布容积为 4650 L。这些参数的个体间变异性分别为 22.98%和 51.48%。
即使在治疗药物监测的情况下，对于环孢素浓度不在治疗范围内的患者，使用本模型结合 CYP3A5 基因分型计算环孢素剂量是可能的。
