中国成年肝移植患者中他克莫司浓度-时间曲线下面积估算的有限采样策略

Limited Sampling Strategy for the Estimation of Tacrolimus Area Under the Concentration-Time Curve in Chinese Adult Liver Transplant Patients.

作者信息

Liu Xiao-Xue, Xu Bei-Ming, Chen Hao, Song Yan-Yan, Yang Wan-Hua, Chen Bing

机构信息

Department of Pharmacy, Ruijin Hospital, Shanghai, PR China.

出版信息

Pharmacology. 2016;98(5-6):229-241. doi: 10.1159/000445896. Epub 2016 Jul 23.

DOI:10.1159/000445896

PMID:27449772

Abstract

OBJECTIVES

Limited sampling strategies (LSS) have been proposed as an alternative method for estimating area under concentration-time curve (AUC) of immunosuppressive agent tacrolimus (TAC). In this study, we aimed to develop the LSS models for predicting AUC of TAC in Chinese liver transplant patients.

METHODS

Twenty-eight adult liver transplant patients receiving immunosuppressive regimen including TAC were enrolled. A total of 47 pharmacokinetic profiles were obtained after 1 or 3 weeks therapy. TAC concentrations were determined before dose (0 h) and at 1, 1.5, 2, 2.5, 3, 4, 6, 8 and 12 h after dosing by LC-MS/MS assay. Optimal subset regression analysis was used to establish the models for estimating TAC AUC0-12. Prediction error (PE) and absolute PE were calculated. The agreement between predicted and measured AUC0-12 was investigated by Bland-Altman analysis. The obtained models were validated by bootstrap analysis. The prediction performance among various CYP3A5 and ABCB1 genotypes was compared. The models selected from previous published studies were also validated using our data.

RESULTS

Twenty-eight models including 1, 2, 3 and 4 blood time points sampling were established (r2 = 0.653-0.979). The best model for prediction of TAC AUC0-12 was 0.81 + 1.73C1 + 1.32C2 + 3.87C4 + 3.75C8 (r2 = 0.979). Forty profiles (85.1%) had estimated TAC AUC0-12 within ±15% of observed TAC AUC0-12. Model with C0-C2 (r2 = 0.880) can be used for outpatients who need monitoring to be carried out in a short period. We also found that ABCB1 genotype may be a reason of variation in the prediction performance. There was good correlation between predicted and measured AUC0-12 (r2 = 0.880-0.928) by using models from previous studies with sample collected within 4 h post dose.

CONCLUSION

The LSS is an effective approach for estimation of full TAC AUC0-12 in Chinese liver transplant patients.

摘要

目的

有限采样策略（LSS）已被提出作为估算免疫抑制剂他克莫司（TAC）浓度-时间曲线下面积（AUC）的一种替代方法。在本研究中，我们旨在建立用于预测中国肝移植患者TAC的AUC的LSS模型。

方法

纳入28例接受包括TAC在内的免疫抑制方案的成年肝移植患者。在治疗1周或3周后共获得47份药代动力学数据。通过液相色谱-串联质谱法测定给药前（0小时）以及给药后1、1.5、2、2.5、3、4、6、8和12小时的TAC浓度。采用最优子集回归分析建立估算TAC的AUC0-12的模型。计算预测误差（PE）和绝对PE。通过Bland-Altman分析研究预测的和实测的AUC0-12之间的一致性。通过自抽样分析对所得模型进行验证。比较不同CYP3A5和ABCB1基因型之间的预测性能。还使用我们的数据对先前发表的研究中选择的模型进行了验证。

结果

建立了包括1、2、3和4个血药时间点采样的28个模型（r2 = 0.653 - 0.979）。预测TAC的AUC0-12的最佳模型为0.81 + 1.73C1 + 1.32C2 + 3.87C4 + 3.75C8（r2 = 0.979）。40份数据（85.1%）估算的TAC的AUC0-12在观察到的TAC的AUC0-12的±15%范围内。含C0 - C2的模型（r2 = 0.880）可用于需要在短时间内进行监测的门诊患者。我们还发现ABCB1基因型可能是预测性能差异的一个原因。使用先前研究中的模型，对于给药后4小时内采集的样本，预测的和实测的AUC0-12之间存在良好的相关性（r2 = 0.880 - 0.928）。