Evaluation of the predictive ability of individualized drug administration adjuvant decision-making system JPKD for tacrolimus blood concentration in kidney transplant recipients
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摘要:
目的 分析个体化给药辅助决策系统Java PK® for Desktop（JPKD）对肾移植受者他克莫司血药浓度的预测能力及影响因素。 方法 收集149例肾移植术后早期受者他克莫司血药浓度监测数据，使用JPKD预测他克莫司剂量调整后的血药谷浓度，计算实测浓度与预测浓度之间的绝对值权重偏差和相对预测误差。使用单因素和多因素logistic回归分析影响绝对权重偏差的相关因素，并绘制受试者工作特征（ROC）曲线评价影响因素对软件预测准确性的判断价值。 结果 收集149例患者266例次血药浓度数据，他克莫司血药浓度实测值为（6.5±3.0）ng/mL（1.1~16.6 ng/mL），JPKD进行计算的预测值为（5.6±2.5）ng/mL（1.4~14.4 ng/mL），计算结果的绝对权重偏差为28.38%，相对预测误差为−13.55%。单因素分析显示性别、白蛋白、红细胞比容变化、细胞色素P450（CYP）3A5*3基因型、C3435T基因型与预测结果不准确有关。多因素logistic回归分析显示CYP3A5*3基因型为AA、红细胞比容变化是影响JPKD预测他克莫司血药浓度准确性的独立危险因素。ROC曲线分析显示，红细胞比容变化>2.25%时，软件预测不准确的风险增加。 结论 JPKD用于预测肾移植受者他克莫司血药浓度具有一定的准确性，可以提高血药浓度的达标率，但CYP3A5*3基因型、红细胞比容变化会影响预测的准确性。 Abstract:Objective To evaluate the predictive ability and influencing factors of individualized drug administration adjuvant decision-making system Java PK® for Desktop (JPKD) for tacrolimus blood concentration in kidney transplant recipients. Methods The monitoring data of tacrolimus blood concentration from 149 recipients early after kidney transplantation were collected. The trough blood concentration of tacrolimus was predicted by JPKD. The absolute weighted deviation and relative prediction deviation between the actual and predicted concentration were calculated. The influencing factors of the absolute weighted deviation were analyzed by univariate and multivariate logistic regression analyses, and the predictive values of these influencing factors on the accuracy of software prediction were assessed by delineating the receiver operating characteristic (ROC) curve. Results Two hundred and sixty-six samples of tacrolimus blood concentration data were collected from 149 patients. The measured blood concentration of tacrolimus was (6.5±3.0) ng/mL (1.1-16.6 ng/mL), and the predicted value calculated by JPKD was (5.6±2.5) ng/mL (1.4-14.4 ng/mL). The absolute weighted deviation of the calculated data was 28.38%, and the relative prediction deviation was −13.55%. Univariate analysis showed that gender, albumin, changes in hematocrit, cytochrome P450 (CYP)3A5*3 genotype and C3435T genotype were associated with the inaccurate prediction results. Multivariate logistic regression analysis found that CYP3A5*3 genotype of AA and the changes in hematocrit were the independent risk factors affecting the accuracy of tacrolimus blood concentration predicted by JPKD. ROC curve analysis showed that when the changes in hematocrit exceeded 2.25%, the risk of inaccurate software prediction was increased. Conclusions JPKD possesses certain accuracy in predicting the blood concentration of tacrolimus in kidney transplant recipients, which may improve the qualified rate of tacrolimus blood concentration. Nevertheless, CYP3A5*3 genotype and the changes of hematocrit may affect the accuracy of predictions. -
图 1 红细胞比容变化评估JPKD软件预测他克莫司血药浓度准确性的ROC曲线
Figure 1. ROC curve of hematocrit value change to evaluate the accuracy of JPKD software in predicting tacrolimus blood concentration
表 1 JPKD预测他克莫司血药浓度准确性的影响因素单因素分析
Table 1. Univariate analysis of factors affecting the accuracy of tacrolimus blood concentration predicted by JPKD
指标 预测准确组（n=167） 预测不准确组（n=99） 统计值 P值 性别[n（%）] 1.852 0.174 男 97（58） 49（49） 女 70（42） 50（51） 年龄[M（P25,P75），岁] 34（30，41） 33（27，41） −1.024 0.306 身高（$\overline x \pm s $，cm） 165±8 164±7 0.789 0.431 体质量[M（P25,P75），kg] 56（51，63） 55（50，60） −1.276 0.202 体质量指数[M（P25,P75），kg/m2] 20（19，22） 20（19，22） −0.553 0.580 供者类型[n（%）] 0.679 0.410 尸体 24（14） 18（18） 亲属活体 143（86） 81（82） 移植术后时间[M（P25,P75），d] 9（7，12） 8（7，12） −0.095 0.924 丙氨酸转氨酶[M（P25,P75），IU/L] 15（9，25） 13（9，24） −0.684 0.494 天冬氨酸转氨酶[M（P25,P75），IU/L] 13（11，18） 13（10，17） −0.919 0.358 碱性磷酸酶[M（P25,P75），IU/L] 61（50，79） 62（48，79） −0.341 0.733 胆红素[M（P25,P75），μmol/L] 9（7，11） 9（7，11） −0.655 0.512 白蛋白[M（P25,P75），g/L] 33（31，37） 34（32，37） −1.491 0.136 白蛋白变化[M（P25,P75），g/L] 2.7（1.3，5.2） 2.4（1.1，4.5） −0.458 0.647 血清肌酐[M（P25,P75），μmol/L] 89（73，120） 89（66，112） −1.178 0.239 白细胞[M（P25,P75），×109/L] 9（7，12） 9（7，11） −0.024 0.981 红细胞比容（$\overline x \pm s $） 0.26±0.06 0.26±0.06 −0.507 0.612 红细胞比容变化[M（P25,P75），%] 1.4（0.7，2.3） 2.1（1.0，3.4） −3.177 0.001 血小板（$\overline x \pm s $，×109/L） 212±74 213±55 −0.198 0.844 CYP3A5*3基因型[n（%）] 4.928 0.085 GG 73（44） 43（44） AG 77（46） 53（54） AA 17（10） 3（3） G2677T/A基因型[n（%）] 1.825 0.873 GG 25（15） 18（18） AA 5（3） 4（4） TT 31（19） 13（13） AT 23（14） 13（13） GA 26（16） 17（17） GT 57（34） 34（34） C3435T基因型[n（%）] 4.101 0.129 CC 61（37） 35（35） CT 73（44） 53（54） TT 33（20） 11（11） C1236T基因型[n（%）] 0.898 0.638 CC 19（11） 14（14） CT 82（49） 51（52） TT 66（40） 34（34） 
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表 2 JPKD预测他克莫司血药浓度准确性的影响因素多因素分析
Table 2. Multivariate analysis of factors affecting the accuracy of tacrolimus blood concentration predicted by JPKD
指标 比值比 95%可信区间 P值 性别 0.627 0.369~1.064 0.084 红细胞比容变化 1.224 1.071~1.400 0.003 白蛋白 1.031 0.969~1.097 0.340 CYP3A5*3 GG 1.000 0.093 CYP3A5*3 AA 0.251 0.066~0.957 0.043 CYP3A5*3 AG 1.099 0.638~1.891 0.734 C3435T CC 1.000 0.149 C3435T CT 1.326 0.749~2.346 0.333 C3435T TT 0.599 0.259~1.388 0.232
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