【摘要】：目的1.以已建立的卡馬西平群體藥代動(dòng)力學(xué)模型和Bayes反饋法為基礎(chǔ),通過(guò)大樣本、不同給藥方案,運(yùn)用EXCEL軟件預(yù)測(cè)卡馬西平的血藥濃度,計(jì)算卡馬西平群體藥代動(dòng)力學(xué)模型對(duì)癲癇患者的血藥濃度預(yù)測(cè)值與實(shí)測(cè)值之間的準(zhǔn)確度、精密度以及一致性,以評(píng)價(jià)卡馬西平群體藥代動(dòng)力學(xué)模型的外部預(yù)測(cè)能力,為臨床運(yùn)用該模型進(jìn)行卡馬西平血藥濃度的預(yù)測(cè)提供研究依據(jù)。2.考察卡馬西平預(yù)測(cè)濃度與患者的發(fā)作頻率及不良反應(yīng)之間的相關(guān)性,為臨床運(yùn)用該模型進(jìn)行個(gè)體化給藥提供一定的理論依據(jù)。方法1.考察卡馬西平群體藥代動(dòng)力學(xué)模型的外部預(yù)測(cè)能力本研究以一年內(nèi)就診于復(fù)旦大學(xué)附屬華山醫(yī)院神經(jīng)內(nèi)科癲癇專病門診的、根據(jù)發(fā)作類型選用卡馬西平或聯(lián)合其他抗癲癇藥物治療的癲癇患者為研究對(duì)象,經(jīng)倫理、知情同意入排后,收集患者的人口學(xué)、病史以及治療藥物等信息,以我科應(yīng)用NONMEM軟件建立的卡馬西平群體藥代動(dòng)力學(xué)模型和Bayes反饋法為基礎(chǔ),運(yùn)用EXCEL軟件計(jì)算大樣本、不同給藥方案下(卡馬西平單藥治療組和卡馬西平聯(lián)合治療組)的患者穩(wěn)態(tài)谷濃度,得到預(yù)測(cè)濃度。在保障患者藥物治療依從性的前提下(即對(duì)患者進(jìn)行用藥依從性宣教,2-4周后復(fù)診,用Morisky依從性量表評(píng)估患者服藥依從性),于患者服用卡馬西平達(dá)穩(wěn)態(tài)時(shí)(即5-7個(gè)血漿半衰期),清晨空腹抽取靜脈血2mL,用熒光偏振免疫法測(cè)定卡馬西平穩(wěn)態(tài)谷濃度,得到實(shí)測(cè)濃度。計(jì)算卡馬西平預(yù)測(cè)濃度相對(duì)于實(shí)測(cè)濃度的平均預(yù)測(cè)誤差和平均絕對(duì)預(yù)測(cè)誤差,考察卡馬西平群體藥代動(dòng)力學(xué)模型外部預(yù)測(cè)能力的準(zhǔn)確度和精密度。當(dāng)絕對(duì)預(yù)測(cè)誤差≤20%時(shí),臨床認(rèn)為這種預(yù)測(cè)值是可以被接受的。同時(shí),采用布蘭德-奧特曼差異圖考察卡馬西平群體藥代動(dòng)力學(xué)模型預(yù)測(cè)濃度和熒光偏振免疫法實(shí)測(cè)濃度的一致性。計(jì)算95%一致性界限,將95%一致性界限作為評(píng)價(jià)兩種測(cè)量方法結(jié)果一致性的指標(biāo)。如果95%一致性界限外的數(shù)據(jù)點(diǎn)數(shù)和95%一致性界限內(nèi)的血藥濃度實(shí)測(cè)值和預(yù)測(cè)值的最大差值絕對(duì)值,是臨床上可以接受的,則認(rèn)為用該模型預(yù)測(cè)濃度和用熒光偏振免疫法實(shí)測(cè)濃度這兩種方法具有較好的一致性,可以互換使用。2.考察卡馬西平預(yù)測(cè)濃度與患者的發(fā)作頻率和不良反應(yīng)之間的相關(guān)性上述入選患者使用《癲癇日歷》記錄發(fā)作頻率,2-4周后復(fù)診,用利物浦不良反應(yīng)量表評(píng)估患者不良反應(yīng)的發(fā)生。采用Pearson相關(guān)分析考察卡馬西平血藥濃度(實(shí)測(cè)濃度和預(yù)測(cè)濃度)與發(fā)作頻率及不良反應(yīng)的相關(guān)性。結(jié)果1.共121位門診癲癇患者參與本研究�？R西平群體藥代動(dòng)力學(xué)模型的平均預(yù)測(cè)誤差和平均絕對(duì)預(yù)測(cè)誤差分別是-4.76%(卡馬西平單藥治療組為-6.18%；卡馬西平聯(lián)合治療組為-2.74%)和14.93%(卡馬西平單藥治療組為15.01%;卡馬西平聯(lián)合治療組為14.80%)。絕對(duì)預(yù)測(cè)誤差≤20%的患者人數(shù)比例為74.38%(卡馬西平單藥治療組為76.06%；卡馬西平聯(lián)合治療組為72.00%)。布蘭德-奧特曼差異圖結(jié)果顯示,只有4.13%(卡馬西平單藥治療組為7.04%；卡馬西平聯(lián)合治療組為0.00%)的數(shù)據(jù)點(diǎn)在95%一致性界限外；在一致性界限范圍內(nèi),使用熒光偏振免疫法測(cè)得的血藥濃度與使用群體藥代動(dòng)力學(xué)模型法預(yù)測(cè)的血藥濃度相比,最大差值的絕對(duì)值為2.44μg/mL(卡馬西平單藥治療組為2.44μg/mL；卡馬西平聯(lián)合治療組為2.41μg/mL)。2.群體藥代動(dòng)力學(xué)模型預(yù)測(cè)的卡馬西平血藥濃度與發(fā)作頻率及不良反應(yīng)均存在正相關(guān)(r=0.132,p=0.001；r=0.236,p=0.009)。結(jié)論1.基于不同的給藥方案,我科建立的卡馬西平群體藥代動(dòng)力學(xué)模型具有較好的外部預(yù)測(cè)能力,可以用于臨床治療,為卡馬西平個(gè)體化給藥提供手段。2.卡馬西平預(yù)測(cè)濃度與發(fā)作頻率及不良反應(yīng)存在正相關(guān),即隨著卡馬西平預(yù)測(cè)血藥濃度的增加,其發(fā)作頻率及不良反應(yīng)的發(fā)生率也隨著增加。這一發(fā)現(xiàn)有助于為臨床應(yīng)用該模型提供實(shí)驗(yàn)數(shù)據(jù),以通過(guò)該模型為患者制定合理的給藥方案。
[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.
【學(xué)位授予單位】：復(fù)旦大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R96

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