Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
Ther Drug Monit. 2011 Dec;33(6):673-80. doi: 10.1097/FTD.0b013e318235a5df.
The aim of this study was to develop and validate limited sampling strategies for accurately predicting 12-hour area under the concentration-time curve (AUC(0-12 h)) to provide a practical method for more precise therapeutic drug monitoring of cyclosporine A in stem cell transplant patients. Steady-state cyclosporine blood concentrations were measured within a dosing interval (12 hours post administration) in 35 allogeneic bone marrow transplant patients receiving 238 mg (±117 mg) twice-daily dose of cyclosporine. Limited sampling strategies were developed by multiple linear regression analysis of relationship between cyclosporine A full AUC(0-12 h) values and different combinations of preselected blood concentrations. Validation of the estimating equations was done by a bootstrap-like cross-validation method. Cross-validation results showed that cyclosporine AUC(0-12 h) could be estimated using either 2 or 3 samples within the first 4 hours after drug administration with good accuracy and precision (absolute prediction error of less than 6.2%). The number of estimated area under the drug concentration-time curves within 15% of observed values was greater than 26 (74%) for models used predose concentration with either c(2h) and c(4h) or both. Most of the previously reported single-sample models showed a systematic error in predicting AUC(0-12 h). Although a statistically significant difference in precision of prediction was seen between 3-sample model using c(0), c(2h), and c(4h) and 2-sample models (c(0), c(2h) or c(0), and c(4h)), such a difference (2%) could not be of clinical importance. Other 2-sample estimating equations (models using c(2h) with either c(6h) or c(10h)) with the same degree of precision appear to be less feasible clinically. Cyclosporine AUC(0-12 h) in bone marrow transplant patients could be estimated using 2 or 3 samples within the first 4 hours after drug administration with good accuracy and precision.
本研究旨在开发并验证有限采样策略，以准确预测环孢素 A 的 12 小时 AUC（0-12 h），为干细胞移植患者的环孢素 A 更精确的治疗药物监测提供实用方法。在 35 例接受 238mg（±117mg）每日 2 次剂量的异基因骨髓移植患者中，在给药间隔内（给药后 12 小时）测量稳态环孢素血药浓度。通过多元线性回归分析环孢素 A 全 AUC（0-12 h）值与预选血药浓度的不同组合之间的关系，开发了有限采样策略。通过自举交叉验证方法验证估算方程的验证。交叉验证结果表明，在给药后前 4 小时内，使用 2 或 3 个样本可以很好地准确和精确地估计环孢素 AUC（0-12 h）（绝对预测误差小于 6.2%）。对于使用预给药时的 c（2h）和 c（4h）或两者的模型，估计的药物浓度-时间曲线下面积在观察值的 15%以内的数量大于 26（74%）。大多数先前报道的单样本模型在预测 AUC（0-12 h）时存在系统误差。虽然使用 c（0）、c（2h）和 c（4h）的 3 样本模型与 2 样本模型（c（0）、c（2h）或 c（0）和 c（4h））之间的预测精度存在统计学差异，但这种差异（2%）可能没有临床意义。其他具有相同精度的 2 样本估算方程（使用 c（2h）的模型，分别与 c（6h）或 c（10h）一起使用）在临床上似乎不太可行。在骨髓移植患者中，使用给药后前 4 小时内的 2 或 3 个样本，可以很好地准确和精确地估计环孢素 AUC（0-12 h）。
