重度海洋性貧血患者服用地拉羅司之劑量與穩態藥物血中濃度關聯性探討

Relationship of Deferasirox Doses and Steady-State Serum Concentrations in Thalassemia Major Patients

郭佩欣(Pei-Hsin Kuo)

指導教授 ： 吳姿樺

臺北醫學大學/藥學院/藥學研究所/碩士(2012年)

摘要

重度海洋性貧血患者終生需要定期的輸血治療而導致病患體內鐵質過度負荷，因而需要接受適當之鐵螯合劑治療，以減少發生致命性併發症的風險。地拉羅司（deferasirox，DEFR）為每日一次口服的鐵螯合劑，過去研究指出多數病人可減少體內鐵質的累積；然而，有少部份病患使用地拉羅司治療後，未能改善其體內鐵質之過度負荷。本研究動機在於建立該藥物分析方法，並應用於接受地拉羅司治療之重度海洋性貧血患者，進行穩態地拉羅司及其鐵螯合物（Fe-[DEFR]2）之療劑監測與評估，以作為未來病患個體化治療之參考。研究方法：利用高效液相層析儀搭配紫外光檢測器建立可同時分析地拉羅司及其鐵螯合物之分析系統，繼而應用於接受地拉羅司治療至少三個月以上之重度海洋性貧血患者，分析其服藥前與服藥後兩小時之穩態地拉羅司血中濃度(CDEFR)、穩態地拉羅司鐵螯合物血中濃度(CFe-[DEFR]2)；所收錄之病患需完成一週用藥紀錄表以追蹤確認其服藥順從性，再以Pearson correlation統計分析藥物血中濃度（CDEFR、CFe-[DEFR]2、CDEFR＋Fe-[DEFR]2）與劑量或患者當日血清儲鐵蛋白（serum ferritin，SF）檢驗數值之相關性。研究結果：本研究所建立之DEFR、Fe-[DEFR]2之藥物分析系統符合確效標準，且最低可定量濃度為5.36與0.63 μmole/L。所收錄之病患（n = 21，平均年齡26.1 ± 5.7歲）服藥後2小時，所測得之CDEFR或CDEFR＋Fe-[DEFR]2與病患每公斤體重所投與的DEFR毫克劑量（mg/kg）具有顯著相關性（p < 0.05）；且CDEFR＋Fe-[DEFR]2與病患所投與的總毫克劑量（mg）也具有顯著相關性（p < 0.05）。服藥前與服藥後2小時之總藥物 （DEFR＋Fe-[DEFR]2）經總劑量校正後之藥物血中濃度（C/D比值）平均值分別為50.87 ± 34.20 μmole/L/g（7.57~166.28）與99.56 ± 44.12 μmole/L/g（44.22~220.18）。排除掉2位病患後，DEFR、Fe-[DEFR]2以及總藥物（DEFR＋Fe-[DEFR]2）經總劑量校正後之藥物血中濃度（C/D比值）與患者當日SF檢驗數值皆無顯著相關性（n = 19）；比較各項平均C/D比值，僅服藥後2小時Fe-[DEFR]2之平均C/D比值在病患SF較高族群有較低趨勢：在SF（μg/mL）小於1000（n = 4）、介於1000~2500（n = 11）與大於2500（n = 4）之各病患族群，其平均C/D比值分別為5.71 ± 1.03、4.79 ± 1.61與3.70 ± 1.22 μmole/L/g。結論：本研究所建立之DEFR與Fe-[DEFR]2分析方法可應用於重度海洋性貧血患者之臨床療劑監測，服藥後2小時之CDEFR或CDEFR＋Fe-[DEFR]2與劑量有顯著關聯性，但各藥物血中濃度經總劑量校正之數值分佈情形顯示具個體差異；服藥後2小時地拉羅司鐵螯合物經總劑量校正之血中濃度偏低是否能應用於藥效預測，則需進一步的研究。

關鍵字

海洋性貧血 ； 地拉羅司 ； 地拉羅司鐵螯合物 ； 療劑監測 ； 血清儲鐵蛋白

並列摘要

β-thalassemia major is a hereditary anemic disease and lifelong transfusion is required for the patients. With development of iron overload, appropriate iron chelation therapy is essential for reducing the risk of life-threatening complications. Deferasirox (DEFR) is a once-daily, orally administered iron chelator and is reported to produce a net negative iron balance; however, there are some patients are not fully responded to this drug. Current study aimed to develop therapeutic drug monitoring (TDM) of DEFR and deferasirox iron(Ⅲ) complex (Fe-[DEFR]2) by an analytical system for thalassemia major patients. Methods: The analytical system consisting of high performance liquid chromatography (HPLC) coupled with UV detector was used for concentration analysis of DEFR and Fe-[DEFR]2 in β-thalassemia major patients treated with deferasirox for at least 3 months. Patients were requested to document the compliance of deferasirox prior to serum collections and steady-state levels of DEFR (CDEFR) and Fe-[DEFR]2 (CFe-[DEFR]2) at trough and 2-hour post-dose were then determined. Pearson correlation coefficient was used to test relationship between serum concentrations and doses or serum ferritin (SF). Result: The analytical methodology was validated for standards of deferasirox and Fe-[deferasirox]2. Lower limit of quantitation were found to be 5.36 and 0.63 μmole/L, respectively. The CDEFR and CDEFR＋Fe-[DEFR]2 of recruited patients (n = 21) at 2-hour post-dose were significantly correlated with doses in mg per kg (p < 0.05). The CDEFR＋Fe-[DEFR]2 was also significantly correlated with total daily dose (mg) (p < 0.05). Mean concentrations of total levels (DEFR+ Fe-[DEFR]2) normalized by total daily dose (C/D ratio) at trough and 2-hour post-dose were 50.87 ± 34.20 μmole/L/g (7.57~166.28) and 99.56 ± 44.12 μmole/L/g (44.22~220.18), respectively. After two patients were excluded, the C/D ratios of DEFR, Fe-[DEFR]2, and total levels were not significantly correlated with SF (n = 19). However, The Fe-[DEFR]2 concentrations at 2-hour post-dose decreased while SF increased. The mean C/D ratios of Fe-[DEFR]2 at 2-hour post-dose for patients whose SF (μg/mL) values less than 1000 (n = 4), in between 1000 and 2500 (n = 11), and higher than 2500 (n = 4), were 5.71 ± 1.03, 4.79 ± 1.61, and 3.70 ± 1.22 μmole/L/g, respectively. Conclusion: The established analytical system for DEFR and Fe-[DEFR]2 can be applied for therapeutic drug monitoring in β-thalassemia major patients. The steady-state CDEFR or CDEFR＋Fe-[DEFR]2 at 2-hour post-dose were significantly correlated with the DEFR doses; however, the wide distribution of individual concentrations normalized by doses indicates an inter-individual variability. Further studies on therapeutic drug monitoring of Fe-[DEFR]2 for drug response prediction are still warranted.

並列關鍵字

thalassemia ； deferasirox ； deferasirox iron(Ⅲ) complex ； therapeutic drug monitoring ； serum ferritin

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