Division of General Pediatric Surgery, Department of Surgery, Centre Hospitalier Universitaire Sainte-Justine, Montreal, Canada.
Ther Drug Monit. 2011 Aug;33(4):380-6. doi: 10.1097/FTD.0b013e318220bc64.
To develop and validate limited sampling strategies (LSSs) for tacrolimus in pediatric liver transplant recipients.
Thirty-six 12-hour pharmacokinetic profiles from 28 pediatric liver transplant recipients (0.4-18.5 years) were collected. Tacrolimus concentrations were measured by immunoassay and area under the curve (AUC0-12) was determined by trapezoidal rule. LSSs consisting of 1, 2, 3, or 4 concentration-time points were developed using multiple regression analysis. Eight promising models (2 per category) were selected based on the following criteria: r2 ≥ 0.90, inclusion of trough concentration (C0), and time points within 4 hours postdose. The predictive performance of these LSSs was evaluated in an independent set of data by measuring the mean prediction error and the root mean squared prediction error.
Five models including 2-4 time points predicted AUC0-12 with a ±15% error limit. Bias (mean prediction error) and precision (root mean squared prediction error) of LSS involving C0, C1, and C4 (AUCpredicted = 9.30 + 3.69 × C0 + 2.19 × C1 + 4.69 × C4) were -4.98% and 8.29%, respectively. Among single time point LSSs, the model using C0 had a poor correlation with AUC0-12 (r2 = 0.53), whereas the one with C4 had the highest correlation with tacrolimus exposure (r2 = 0.84).
Trough concentration is a poor predictor of tacrolimus AUC0-12 in pediatric liver transplant recipients. However, LSSs using 2-4 concentration-time points obtained within 4 hours postdose provide a reliable and convenient method to predict tacrolimus exposure in this population. The proposed LSSs represent an important step that will allow the undertaking of prospective trials aiming to better define tacrolimus target AUC in pediatric liver transplant recipients and to determine whether AUC-guided monitoring is superior to C0-based monitoring in terms of efficacy and safety.
开发并验证儿童肝移植受者他克莫司的简化采样策略（LSS）。
收集 28 名儿童肝移植受者（0.4-18.5 岁）的 36 个 12 小时药代动力学曲线。通过免疫测定法测量他克莫司浓度，并通过梯形规则确定 AUC0-12。使用多元回归分析开发由 1、2、3 或 4 个浓度-时间点组成的 LSS。根据以下标准从 8 种有前途的模型（每类 2 种）中选择：r2≥0.90，包含谷浓度（C0），以及给药后 4 小时内的时间点。通过测量平均预测误差和均方根预测误差，在独立数据集上评估这些 LSS 的预测性能。
包括 2-4 个时间点的 5 个模型可以以±15%的误差限制预测 AUC0-12。涉及 C0、C1 和 C4 的 LSS 的偏差（平均预测误差）和精度（均方根预测误差）分别为-4.98%和 8.29%（AUCpredicted=9.30+3.69×C0+2.19×C1+4.69×C4）。在单时间点 LSS 中，使用 C0 的模型与 AUC0-12 的相关性较差（r2=0.53），而使用 C4 的模型与他克莫司暴露的相关性最高（r2=0.84）。
谷浓度是儿童肝移植受者他克莫司 AUC0-12 的不良预测指标。然而，在给药后 4 小时内获得的 2-4 个浓度-时间点的 LSS 可提供一种可靠且方便的方法来预测该人群中的他克莫司暴露情况。所提出的 LSS 是向前迈出的重要一步，这将使进行前瞻性试验成为可能，旨在更好地定义儿童肝移植受者他克莫司的目标 AUC，并确定 AUC 指导监测在疗效和安全性方面是否优于基于 C0 的监测。
