肝、肾和心脏移植受者中速释和缓释他克莫司制剂的群体药代动力学。
Population pharmacokinetics of immediate- and prolonged-release tacrolimus formulations in liver, kidney and heart transplant recipients.
机构信息
Astellas Pharma Global Development, Inc., Northbrook, Illinois, USA.
Formerly Astellas Pharma Global Development, Inc., Northbrook, Illinois, USA.
出版信息
Br J Clin Pharmacol. 2019 Aug;85(8):1692-1703. doi: 10.1111/bcp.13952. Epub 2019 Jun 7.
AIMS
Develop a population pharmacokinetics model of tacrolimus in organ transplant recipients receiving twice-daily, immediate-release (IR-T; Prograf) and/or once-daily, prolonged-release (PR-T; Advagraf or Astagraf XL) tacrolimus.
METHODS
Tacrolimus concentration-time profiles were analysed from 8 Phase II studies in adult and paediatric liver, kidney and heart transplant patients receiving IR-T and/or PR-T. A tacrolimus population pharmacokinetic model, including identification of significant covariates, was developed using NONMEM.
RESULTS
Overall, 23,176 tacrolimus concentration records were obtained from 408 patients. A 2-compartment model with first-order absorption and elimination described the concentration-time profiles. Tacrolimus absorption rate was 50% slower with PR-T vs IR-T. Tacrolimus apparent oral clearance was 44.3 L/h in Whites and 59% higher in Asians. Tacrolimus central volume of distribution was 108 L in males and 55% lower in females; trough concentrations were similar between formulations. Tacrolimus relative bioavailability was similar between formulations (geometric mean ratio PR-T:IR-T 95%, 90% confidence intervals: 89%, 101%). Asians had 83% and 51% higher relative bioavailability than Whites and Blacks, respectively, for IR-T and PR-T. Whites had 49% and 77% higher relative bioavailability than Blacks for PR-T and IR-T, respectively. Blacks had 52% lower relative bioavailability than Whites and Asians for IR-T and PR-T. Type of organ transplanted and patient population (adult/paediatric) did not have a significant effect on tacrolimus pharmacokinetics.
CONCLUSIONS
This population pharmacokinetic model described data from transplant recipients who received IR-T and/or PR-T. Tacrolimus trough concentrations and relative bioavailability were similar between formulations, supporting 1 mg:1 mg conversion from Prograf to Advagraf/Astagraf XL in clinical practice.
目的
建立一种群体药代动力学模型，用于研究接受每日两次普通释放（IR-T；普乐可复）和/或每日一次延长释放（PR-T；Advagraf 或 Astagraf XL）他克莫司的器官移植受者的他克莫司药代动力学。
方法
对接受 IR-T 和/或 PR-T 的成人和儿科肝、肾和心脏移植患者的 8 项 II 期研究中的他克莫司浓度-时间曲线进行分析。采用 NONMEM 建立包括确定重要协变量的他克莫司群体药代动力学模型。
结果
共有 408 名患者的 23176 个他克莫司浓度记录。采用 2 室模型和一级吸收和消除描述浓度-时间曲线。与 IR-T 相比，PR-T 的他克莫司吸收速率慢 50%。白人的他克莫司表观口服清除率为 44.3 L/h，亚洲人的清除率高 59%。男性的他克莫司中央分布容积为 108 L，女性低 55%；两种制剂的谷浓度相似。两种制剂的他克莫司相对生物利用度相似（PR-T：IR-T 的几何均数比值 95%，90%置信区间：89%，101%）。与白人相比，亚洲人的 IR-T 和 PR-T 相对生物利用度分别高 83%和 51%，而与黑人相比，亚洲人的 IR-T 和 PR-T 相对生物利用度分别高 51%和 83%。与黑人相比，白人的 PR-T 和 IR-T 相对生物利用度分别高 49%和 77%。移植的器官类型和患者人群（成人/儿科）对他克莫司的药代动力学没有显著影响。
结论
该群体药代动力学模型描述了接受 IR-T 和/或 PR-T 的移植受者的数据。两种制剂的他克莫司谷浓度和相对生物利用度相似，支持在临床实践中将普乐可复转换为 Advagraf/Astagraf XL 时采用 1 mg:1 mg 的转换。
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