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研究生:黃輝慶
研究生(外文):Hui-Ching Huang
論文名稱:建立群體藥動學模式用於評估精神病患者丙戊酸之清除率
論文名稱(外文):Establishment of a population pharmacokinetic model to estimate valproic acid clearance in psychiatric patients
指導教授:曾應龍曾應龍引用關係
指導教授(外文):Ying-Lung Tseng
學位類別:碩士
校院名稱:慈濟大學
系所名稱:藥理暨毒理學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2006
畢業學年度:94
語文別:英文
論文頁數:68
中文關鍵詞:群體藥物動力學丙戊酸精神病患者
外文關鍵詞:psychiatric patientspopulation pharmacokineticsNONMEMvalproic acid
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自從1970年代以來,丙戊酸 (Valproic acid; VPA) 一直是臨床上用以治療癲癇的藥物,目前則是被美國食品藥物管理局(FDA)核準,用於治療失神及混合型癲癇(absence seizures,mixed seizures)以及精神科方面雙極性情感疾患的躁症(bipolar I disorder, manic phase)。研究顯示,VPA用於治療躁症患者的療效與副作用和其血中濃度具相關性,有效治療濃度介於45 - 100 mg/mL之間,血中藥物濃度高於100 mg/mL或日劑量大於1800毫克則易產生副作用 (Bowden et al.,1996)。
本研究之目的在評估臺灣精神病患者對VPA之清除率 (clearance)。研究過程中收集符合收案條件之精神病患者臨床上常規監測VPA之血清,紀錄其用藥史、年齡、身高、體重及 blood urea nitrogen (BUN)、creatinine、albumin等相關生化值。以群體藥物動力學模式(Population Pharmacokinetic Nonlinear Mixed Effect Model; NONMEM Program)單一室模型(one-compartment model)分析上述因子對VPA清除率之影響。血清中之VPA濃度以螢光免疫分析儀 ( Fluorescence Polarization Immunoassay ; FPIA ) TDX FLx, ABBOTT進行分析。
群體藥物動力學分析結果:VPA清除率之方程式為: CL(L/h) = 0.185 + (0.478 / 280.5) × 0.25 × Dose + (0.0660 / 38.7) × AGE.
方程式Cpss pre = 0.0500 × Dose / CL 及 Cpss pre = 0.0556 × Dose / CL可分別用以預測每日服用一般劑型VPA四次或每日服用緩釋劑型VPA一至兩次的臺灣精神病患者服藥到達穩定狀態(steady-state)時的血中藥物濃度及決定最佳劑量。上述方程式中的CL(L/h)是病人對VPA的清除率,Dose代表病人服用VPA的日劑量,AGE是病人的年齡,Cpss pre則代表預測精神病患者服藥到達穩定狀態(steady-state)時的血中藥物濃度。
以另外兩組分別是十位及二十位病人驗證上述方程式的準確性與應用性,得到滿意之結果。透過藥動學的方法可預給最佳之藥物劑量,以達到最適當之穩定血中藥物濃度,相較於傳統之經驗性給藥方式,除可縮短嘗試劑量調整所需時間外,更能確保療效,避免副作用,尤其是自我照護能力較低的精神病患者。

關鍵詞:丙戊酸(Valproic Acid)、群體藥物動力學(Population Pharmacokinetic Nonlinear Mixed Effect Model; NONMEM )、精神病患者 (Psychiatric patients)
Background: Valproic acid (VPA; valproate) is a drug that has been widely used as an anticonvulsant since the 1970s. VPA is currently approved by the FDA (USA) for the treatment of absence seizures, mixed seizures, and bipolar I disorder, manic phase. The efficacy and toxicity of VPA in patients with bipolar disorders are associated with serum VPA concentration. VPA serum levels between 45 and 100-125 mg/L are much more likely to have efficacious and well-tolerated response. Toxic effects are frequently associated with daily doses over 1800 mg or blood levels over 100 mg/L .The aim of this study is to construct a formula intended to estimate VPA clearance in routine clinical care of a population of psychiatric patients in Taiwan.

Methods: Prospective steady state serum concentration data (n=534) collected from 109 adult psychiatric patients who have been receiving VPA were studied. Data were analyzed according to a one-compartment model using the NONMEM program. Several possible influential parameters, such as VPA daily dose, gender, age, height, total body weight, BUN, creatinine and albumin were investigated.
Results: In this study, a wide inter-individual variability was found to be present in drug dose and serum concentration distribution. The final regression model established for VPA clearance (CL) was as follows:
CL(L/h) = 0.185+ (0.478 / 280.5) × 0.25 × Dose + (0.0660 / 38.7) × AGE.
Validation of the established model was carried out by 10 psychiatric patients. The results demonstrated that Equation Cpss pre = 0.0500 × Dose / CL showed the least biased and more accurate in predicting the steady state serum VPA concentration in psychiatric patients who ingested non-sustained-release VPA formulation four times a day. In addition, another group consisting of 20 patients who ingested sustained-release VPA was also tested using the established model. The results showed the best prediction power obtained was Equation Cpss pre = 0.0556 × Dose / CL. In the Equations, Dose indicates the total daily dose (mg) of VPA, Cpss pre represent prediction serum concentration at steady state.

Conclusions: This model may be used for a priori recommendation and dose optimization of VPA administration in Taiwanese psychiatric patients. In contrast to traditional practice on determining a proper drug dose based on experience, this model not only reduces time on looking for a suitable drug dose for a patient, but also ensures treatment effects and avoids side effects, in particular to those patients who have difficulties on self-care.
1. Introduction
1.1 Background and significance ----------------------------------------- 1
1.1.1 Valproic acid ----------------------------------------------------- 1
1.1.2 Action and clinical application of VPA -------------------------- 1
1.1.3 Level of VPA in serum --------------------------------------------- 3
1.1.4 Pharmacokinetics of VPA ------------------------------------------ 3
1.1.5 Prescription dose of VPA ------------------------------------------ 3

1.2 Pharmacokinetic model ----------------------------------------------- 4
1.2.1 One compartment open model ---------------------------------- 4
1.2.2 Population pharmacokinetics -------------------------------------5
1.2.3 Basic principles of population analysis --------------------------6
1.2.4 Nonlinear mixed effects model and
PDx-Pop software ---------------------------------------------------- 7

1.3 Measurement of VPA concentration in plasma ---------------------- 7
1.3.1 Fluorescence polarization immunoassay (FPIA) -------------- 7

1.4 Purpose ------------------------------------------------------------- 8
1.4.1 Specific aims ----------------------------------------------------- 8

2 Experimental
2.1 Materials ----------------------------------------------------------- 8
2.1.1 Drugs ------------------------------------------------------------- 8
2.1.2 Reagents and solutions -------------------------------------------- 9
2.1.3 Instrumentation --------------------------------------------------- 9

2.2 Methods --------------------------------------------------------------9
2.2.1 Subjects -----------------------------------------------------------9
2.2.2 Subject grouping ---------------------------------------------------10
2.2.3 Drug administration ------------------------------------------------11
2.2.4 Sample collection --------------------------------------------------11
2.2.5 Sample preparation -------------------------------------------------11



Page
2.2.6 Determination of VPA concentration in serum -------------- 11
2.2.7 Population pharmacokinetic analysis -------------------------- 12
2.2.8 Validation of the pharmacokinetic model ---------------------------13

3 Results
3.1 A wide inter-individual variability occurred in drug
dose and serum concentration distribution ------------------------- 16
3.2 The final regression model of VPA clearance ------------------------ 16
3.3 Validation of final model and VPA concentration
prediction equations ---------------------------------------------------- 17

4 Discussion ---------------------------------------------------------- 18

5 Conclusion --------------------------------------------------------- 23

6 Tables --------------------------------------------------------------- 24

7 Figures -------------------------------------------------------------- 28

8 References --------------------------------------------------------- 37

9 Appendices-------------------------------------------------------------40
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