INSERM UMR-S850, Limoges, France.
Ther Drug Monit. 2010 Apr;32(2):129-35. doi: 10.1097/FTD.0b013e3181cc70db.
The once-daily formulation of tacrolimus has been reported to exhibit the same efficacy and safety profile as compared with the immediate-release form administered twice daily. However, as a result of differences in their pharmacokinetic (PK) profile, the PK models or Bayesian estimators (MAP-BE) previously developed for the immediate-release formulation cannot be used for the new once-daily formulation. Using the PK information obtained from a Phase II trial, the aim of this study was to explore the feasibility of developing a PK model and a MAP-BE able to estimate, on the basis of a routinely applicable limited sampling strategy, tacrolimus individual PK parameters and AUC0-24h in de novo renal transplant patients given the once-daily formulation.
Twelve de novo kidney transplant recipients receiving once-daily tacrolimus as part of their immunosuppressive regimen provided full PK profiles (17 concentration time points over 24 hours) on Days 14 and 42 posttransplantation. On the basis of a one-compartment open model with absorption described as following a double gamma distribution, a classic iterative two-stage method was applied to develop MAP-BEs. All the limited sampling strategies with a maximum of three sampling times within 4 hours postdose were tested for Bayesian forecasting with the aim of accurately estimating the AUC0-24h.
Once-daily tacrolimus exhibited a high interpatient PK variability with coefficients of variation of 34.3% and 36.2% for AUC0-24h/dose (mg/kg) on Days 14 and 42, respectively. Regression analysis between C0 and AUC0-24h yielded r = 0.68 and 0.76 at these two periods, respectively. The iterative two-stage approach led to the development of a different MAP-BE for each posttransplantation period, which allowed estimation of once-daily tacrolimus pharmacokinetics and AUC0-24h on the basis of a C0-C1h-C3h sampling schedule. The mean bias of the Bayesian versus reference (trapezoidal) AUCs was 4.2% +/- 6.1% (range, -11.8% to +11.2%; root mean square error = 7.1%) on Day 14 and 0.2% +/- 7.9% (range, -12.9% to +14.1%; root mean square error = 7.8%) on Day 42.
A PK model and Bayesian estimators allowing estimation of tacrolimus AUC0-24h based on a routinely applicable limited sampling strategy were developed for once-daily tacrolimus in renal transplantation. Further validation in independent groups of patients is required to confirm their applicability for optimizing the monitoring of once-daily tacrolimus in routine clinical practice or to conduct observational or comparative therapeutic drug monitoring clinical trials.
与每日两次给予的即时释放制剂相比，他克莫司的每日一次制剂已被证明具有相同的疗效和安全性。然而，由于药代动力学（PK）特征的差异，之前为即时释放制剂开发的 PK 模型或贝叶斯估计器（MAP-BE）不能用于新的每日一次制剂。本研究旨在利用 II 期试验获得的 PK 信息，探索开发 PK 模型和 MAP-BE 的可行性，以便基于常规适用的有限采样策略，估算接受每日一次制剂的新诊断肾移植患者的他克莫司个体 PK 参数和 AUC0-24h。
12 例接受每日一次他克莫司作为免疫抑制方案一部分的新诊断肾移植受者在移植后第 14 和 42 天提供了完整的 PK 谱（24 小时内 17 个浓度时间点）。基于吸收描述为双伽马分布的单室开放模型，应用经典迭代两阶段法开发 MAP-BE。所有最多在给药后 4 小时内进行 3 次采样的有限采样策略均进行了贝叶斯预测测试，以准确估计 AUC0-24h。
每日一次他克莫司的个体 PK 变异性较大，在移植后第 14 和 42 天，AUC0-24h/剂量（mg/kg）的变异系数分别为 34.3%和 36.2%。C0 与 AUC0-24h 之间的回归分析在这两个时期分别产生 r = 0.68 和 0.76。迭代两阶段方法为每个移植后时期开发了不同的 MAP-BE，允许根据 C0-C1h-C3h 采样方案估算每日一次他克莫司的药代动力学和 AUC0-24h。贝叶斯与参考（梯形）AUC 之间的平均偏差为 4.2% +/- 6.1%（范围，-11.8%至+11.2%；均方根误差= 7.1%）在第 14 天和 0.2% +/- 7.9%（范围，-12.9%至+14.1%；均方根误差= 7.8%）在第 42 天。
开发了一种 PK 模型和贝叶斯估计器，允许基于常规适用的有限采样策略估算肾移植中他克莫司的 AUC0-24h。需要在独立的患者组中进一步验证，以确认其在优化日常临床实践中监测每日一次他克莫司或进行观察性或比较治疗药物监测临床试验中的适用性。
