卡马西平PPK模型预测能力的评价与临床应用研究
发布时间：2018-09-15 18:58
【摘要】：目的1.以已建立的卡马西平群体药代动力学模型和Bayes反馈法为基础,通过大样本、不同给药方案,运用EXCEL软件预测卡马西平的血药浓度,计算卡马西平群体药代动力学模型对癫痫患者的血药浓度预测值与实测值之间的准确度、精密度以及一致性,以评价卡马西平群体药代动力学模型的外部预测能力,为临床运用该模型进行卡马西平血药浓度的预测提供研究依据。2.考察卡马西平预测浓度与患者的发作频率及不良反应之间的相关性,为临床运用该模型进行个体化给药提供一定的理论依据。方法1.考察卡马西平群体药代动力学模型的外部预测能力本研究以一年内就诊于复旦大学附属华山医院神经内科癫痫专病门诊的、根据发作类型选用卡马西平或联合其他抗癫痫药物治疗的癫痫患者为研究对象,经伦理、知情同意入排后,收集患者的人口学、病史以及治疗药物等信息,以我科应用NONMEM软件建立的卡马西平群体药代动力学模型和Bayes反馈法为基础,运用EXCEL软件计算大样本、不同给药方案下(卡马西平单药治疗组和卡马西平联合治疗组)的患者稳态谷浓度,得到预测浓度。在保障患者药物治疗依从性的前提下(即对患者进行用药依从性宣教,2-4周后复诊,用Morisky依从性量表评估患者服药依从性),于患者服用卡马西平达稳态时(即5-7个血浆半衰期),清晨空腹抽取静脉血2mL,用荧光偏振免疫法测定卡马西平稳态谷浓度,得到实测浓度。计算卡马西平预测浓度相对于实测浓度的平均预测误差和平均绝对预测误差,考察卡马西平群体药代动力学模型外部预测能力的准确度和精密度。当绝对预测误差≤20%时,临床认为这种预测值是可以被接受的。同时,采用布兰德-奥特曼差异图考察卡马西平群体药代动力学模型预测浓度和荧光偏振免疫法实测浓度的一致性。计算95%一致性界限,将95%一致性界限作为评价两种测量方法结果一致性的指标。如果95%一致性界限外的数据点数和95%一致性界限内的血药浓度实测值和预测值的最大差值绝对值,是临床上可以接受的,则认为用该模型预测浓度和用荧光偏振免疫法实测浓度这两种方法具有较好的一致性,可以互换使用。2.考察卡马西平预测浓度与患者的发作频率和不良反应之间的相关性上述入选患者使用《癫痫日历》记录发作频率,2-4周后复诊,用利物浦不良反应量表评估患者不良反应的发生。采用Pearson相关分析考察卡马西平血药浓度(实测浓度和预测浓度)与发作频率及不良反应的相关性。结果1.共121位门诊癫痫患者参与本研究。卡马西平群体药代动力学模型的平均预测误差和平均绝对预测误差分别是-4.76%(卡马西平单药治疗组为-6.18%；卡马西平联合治疗组为-2.74%)和14.93%(卡马西平单药治疗组为15.01%;卡马西平联合治疗组为14.80%)。绝对预测误差≤20%的患者人数比例为74.38%(卡马西平单药治疗组为76.06%；卡马西平联合治疗组为72.00%)。布兰德-奥特曼差异图结果显示,只有4.13%(卡马西平单药治疗组为7.04%；卡马西平联合治疗组为0.00%)的数据点在95%一致性界限外；在一致性界限范围内,使用荧光偏振免疫法测得的血药浓度与使用群体药代动力学模型法预测的血药浓度相比,最大差值的绝对值为2.44μg/mL(卡马西平单药治疗组为2.44μg/mL；卡马西平联合治疗组为2.41μg/mL)。2.群体药代动力学模型预测的卡马西平血药浓度与发作频率及不良反应均存在正相关(r=0.132,p=0.001；r=0.236,p=0.009)。结论1.基于不同的给药方案,我科建立的卡马西平群体药代动力学模型具有较好的外部预测能力,可以用于临床治疗,为卡马西平个体化给药提供手段。2.卡马西平预测浓度与发作频率及不良反应存在正相关,即随着卡马西平预测血药浓度的增加,其发作频率及不良反应的发生率也随着增加。这一发现有助于为临床应用该模型提供实验数据,以通过该模型为患者制定合理的给药方案。
[Abstract]:OBJECTIVE 1. Based on the established population pharmacokinetic model of carbamazepine and Bayesian feedback method, the serum concentration of carbamazepine was predicted by EXCEL software with large sample and different dosage regimens, and the accuracy and precision between the predicted and measured values of carbamazepine population pharmacokinetic model in epileptic patients were calculated. To evaluate the external predictive ability of the population pharmacokinetic model of carbamazepine, and to provide a basis for clinical application of the model to predict the blood concentration of carbamazepine. 2. To investigate the correlation between the predictive concentration of carbamazepine and the attack frequency and adverse reactions of patients, and to individualize the model for clinical application. Methods 1. To investigate the external predictive ability of the population pharmacokinetic model of carbamazepine. In this study, epileptic patients with epilepsy who were hospitalized in the Department of Epilepsy, Huashan Hospital, Fudan University within one year were selected according to the type of epilepsy and treated with carbamazepine or other antiepileptic drugs. Subjects were selected with ethical and informed consent. The demographic, medical history and therapeutic drug information were collected. Based on the population pharmacokinetic model and Bayes feedback method of carbamazepine established by NONMEM software, large samples were calculated with EXCEL software under different dosage regimens (carbamazepine monotherapy group and carbamazepine monotherapy group). Patients in the combined treatment group were assessed with the Morisky Compliance Scale (MOCS) on the premise of guaranteeing compliance with medication. Patients were given carbamazepine for 5-7 half-lives in the morning on an empty stomach. The average and absolute prediction errors of the predicted concentration of carbamazepine relative to the measured concentration were calculated. The accuracy and precision of the external prediction ability of the population pharmacokinetic model of carbamazepine were investigated. At the same time, the consistency between the predicted concentration of carbamazepine population pharmacokinetic model and the measured concentration by fluorescence polarization immunoassay was investigated by using Brad-Ottoman difference diagram. The 95% consistency limit was calculated and the 95% consistency limit was used as one of the results to evaluate the two methods. If the data points outside the 95% consistency limit and the absolute value of the maximum difference between the measured and predicted blood drug concentrations within the 95% consistency limit are clinically acceptable, then it is considered that the two methods of predicting concentration by this model and measuring concentration by fluorescence polarization immunoassay have good consistency and can be interchanged to make it possible to make it possible to use of this model to predict concentration. 2. To investigate the correlation between predicted concentration of carbamazepine and seizure frequency and adverse reactions. The seizure frequency was recorded by < epilepsy calendar > and the incidence of adverse reactions was assessed by the Liverpool Adverse Reaction Scale 2-4 weeks later. Results 1. A total of 121 outpatients with epilepsy participated in the study. The mean predictive error and mean absolute predictive error of carbamazepine population pharmacokinetic model were - 4.76% (carbamazepine alone group - 6.18%; carbamazepine combined group - 2.74%) and 14.93% (carbamazepine alone group - 6.18%) respectively. The absolute predictive error < 20% was 74.38% (76.06% in carbamazepine alone group and 72.00% in carbamazepine combined group). The absolute value of the maximum difference was 2.44 ug/mL (2.44 ug/mL for carbamazepine monotherapy group) compared with that predicted by the population pharmacokinetic model (2.44 ug/mL for carbamazepine monotherapy group). The serum concentration of carbamazepine predicted by population pharmacokinetic model was positively correlated with attack frequency and adverse reactions (r = 0.132, P = 0.001; r = 0.236, P = 0.009). Conclusion 1. Based on different dosage regimens, the population pharmacokinetic model of carbamazepine established by our department has a good external pharmacokinetic model. The predictive ability of carbamazepine can be used for clinical treatment, providing a means for individual administration of carbamazepine. 2. The predictive concentration of carbamazepine is positively correlated with the frequency of attack and the incidence of adverse reactions. This finding is helpful for clinical application. The model provides experimental data to formulate reasonable dosing regimens for patients through this model.
【学位授予单位】：复旦大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R96
本文编号：2244194
[Abstract]:OBJECTIVE 1. Based on the established population pharmacokinetic model of carbamazepine and Bayesian feedback method, the serum concentration of carbamazepine was predicted by EXCEL software with large sample and different dosage regimens, and the accuracy and precision between the predicted and measured values of carbamazepine population pharmacokinetic model in epileptic patients were calculated. To evaluate the external predictive ability of the population pharmacokinetic model of carbamazepine, and to provide a basis for clinical application of the model to predict the blood concentration of carbamazepine. 2. To investigate the correlation between the predictive concentration of carbamazepine and the attack frequency and adverse reactions of patients, and to individualize the model for clinical application. Methods 1. To investigate the external predictive ability of the population pharmacokinetic model of carbamazepine. In this study, epileptic patients with epilepsy who were hospitalized in the Department of Epilepsy, Huashan Hospital, Fudan University within one year were selected according to the type of epilepsy and treated with carbamazepine or other antiepileptic drugs. Subjects were selected with ethical and informed consent. The demographic, medical history and therapeutic drug information were collected. Based on the population pharmacokinetic model and Bayes feedback method of carbamazepine established by NONMEM software, large samples were calculated with EXCEL software under different dosage regimens (carbamazepine monotherapy group and carbamazepine monotherapy group). Patients in the combined treatment group were assessed with the Morisky Compliance Scale (MOCS) on the premise of guaranteeing compliance with medication. Patients were given carbamazepine for 5-7 half-lives in the morning on an empty stomach. The average and absolute prediction errors of the predicted concentration of carbamazepine relative to the measured concentration were calculated. The accuracy and precision of the external prediction ability of the population pharmacokinetic model of carbamazepine were investigated. At the same time, the consistency between the predicted concentration of carbamazepine population pharmacokinetic model and the measured concentration by fluorescence polarization immunoassay was investigated by using Brad-Ottoman difference diagram. The 95% consistency limit was calculated and the 95% consistency limit was used as one of the results to evaluate the two methods. If the data points outside the 95% consistency limit and the absolute value of the maximum difference between the measured and predicted blood drug concentrations within the 95% consistency limit are clinically acceptable, then it is considered that the two methods of predicting concentration by this model and measuring concentration by fluorescence polarization immunoassay have good consistency and can be interchanged to make it possible to make it possible to use of this model to predict concentration. 2. To investigate the correlation between predicted concentration of carbamazepine and seizure frequency and adverse reactions. The seizure frequency was recorded by < epilepsy calendar > and the incidence of adverse reactions was assessed by the Liverpool Adverse Reaction Scale 2-4 weeks later. Results 1. A total of 121 outpatients with epilepsy participated in the study. The mean predictive error and mean absolute predictive error of carbamazepine population pharmacokinetic model were - 4.76% (carbamazepine alone group - 6.18%; carbamazepine combined group - 2.74%) and 14.93% (carbamazepine alone group - 6.18%) respectively. The absolute predictive error < 20% was 74.38% (76.06% in carbamazepine alone group and 72.00% in carbamazepine combined group). The absolute value of the maximum difference was 2.44 ug/mL (2.44 ug/mL for carbamazepine monotherapy group) compared with that predicted by the population pharmacokinetic model (2.44 ug/mL for carbamazepine monotherapy group). The serum concentration of carbamazepine predicted by population pharmacokinetic model was positively correlated with attack frequency and adverse reactions (r = 0.132, P = 0.001; r = 0.236, P = 0.009). Conclusion 1. Based on different dosage regimens, the population pharmacokinetic model of carbamazepine established by our department has a good external pharmacokinetic model. The predictive ability of carbamazepine can be used for clinical treatment, providing a means for individual administration of carbamazepine. 2. The predictive concentration of carbamazepine is positively correlated with the frequency of attack and the incidence of adverse reactions. This finding is helpful for clinical application. The model provides experimental data to formulate reasonable dosing regimens for patients through this model.
【学位授予单位】：复旦大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R96
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