海洋性貧血患者之地拉羅司療劑監測方法與應用

Development of Analytical Methods for the Therapeutic Drug Monitoring of Deferasirox in Thalassemia Patients

吳文馨(Wen-Hsin Wu)

指導教授 ： 吳姿樺

臺北醫學大學/藥學院/藥學研究所/碩士(2011年)

摘要

重度β-海洋性貧血病患因需要長期輸血而使其患者需要服用鐵螯合劑以避免產生因輸血所導致之鐵質過度負荷併發症。現今鐵螯合劑的研發已進展到只需每日口服一次的地拉羅司 (deferasirox，DEFR)。本研究欲建立有效之藥物分析系統，來分析接受DEFR治療之重度β-海洋性貧血病患之藥物 (含DEFR、Fe–[DEFR]2) 之血中濃度，以期釐清病患鐵質負荷之藥物治療相關問題。研究方法: (一) 以高效液相層析儀搭配紫外光/可見光檢測器，並使用長度15 cm 的C18層析管柱同時分析DEFR與及其三價鐵複合物Fe–[DEFR]2；(二) 本研究收錄已穩定接受DEFR治療的重度海洋性貧血患者 (n=23) 之每月常規的血清鐵蛋白 (serum ferritin，SF) 檢查值，並在本療劑監測試驗時進行服藥前藥物血中濃度(Ctrough)、服藥後2小時之藥物血中濃度 (C2h) 取樣分析；同時利用經詢問病患在接受取樣前五天所得知服藥情形來進行藥物血中濃度與各因子間之相關性探討。研究結果: (一) 本研究所建立之DEFR、Fe–[DEFR]2含內部標準品檢量線以及經固相萃取血漿檢品分析檢量線皆具顯著線性關係，各精密度與準確度亦達規定標準。(二) 將本研究所建立之分析系統應用於病患血漿檢品分析，結果: 依照所給予病患之每公斤劑量之組別來比較各組的C2h-DEFR，結果顯示40 mg/kg組分別高於10 mg/kg、25 mg/kg、30 mg/kg且具顯著差異 (p<0.05)。將藥物血中濃度以測得濃度除以服用每日總劑量(C/D)來表示，所有病患(n=23)之 C2h/D(DEFR+Fe–[DEFR]2) 平均值為22.37±14.28 μmole/L/g (4.91~56.92)，呈現個體間差異；但C2h-DEFR、C2h-Fe–[DEFR]2、服藥2小時後總藥物濃度(C2h-DEFR+C2h-Fe–[DEFR]2) 分別與病患所服用的DEFR總毫克劑量具顯著關聯性 (p<0.05)。已完成用藥紀錄之病患(n=10)平均Ctrough/D(DEFR+Fe–[DEFR]2)為12.30 ±10.04 μmole/L/g (3.59~31.68)；而 SF檢查值小於1000 μg/L的病患(n=4)，其服藥前Ctrough/D(DEFR+Fe–[DEFR]2)與服藥後C2h/D(DEFR+Fe–[DEFR]2)之比值與其停藥時間相除皆有達到0.02 μmole/L/g/h。結論: 本研究所建立之DEFR與Fe–[DEFR]2分析方法應用於病患血漿檢品分析可釐清重度β-海洋性貧血病患之DEFR療效問題；未來仍需更一步的研究以釐清病患個體間影響血中濃度之相關因子。

關鍵字

地拉羅司 ； 療劑監測 ； 海洋性貧血 ； 個體差異

並列摘要

Iron chelation therapy is essential for transfusion-dependent of β-thalassemia major patients, who inevitably develop iron overload complications. In order to improve the patients’ quality of life, once daily oral chelator, deferasirox (DEFR) has been available clinically. We aimed to developed an high-performance liquid chromatography (HPLC) analytical methods for DEFR and Fe–[DEFR]2 in order to apply for therapeutic drug monitoring (TDM) of β-thalassemia major patients and to clarify the DEFR–related problems. Methods : (I) a HPLC coupled with an UV/VIS detector was set up to determine the DEFR and Fe–[DEFR]2 on C18 column；(II) 23 patients with β-thalassemia major receiving DEFR treatment have been recruited and their regular monthly serum ferritin (SF) data was collected. During the trials, blood samples taken right before (trough) and also at 2 hours (2h) after the DEFR administration were subjected for concentration determinations. The correlations between (Ctrough) or C2h and other parameters were analyzed. Results: The concentrations of DEFR, Fe-[DEFR]2 standards, internal standard and peak areas were significantly linear correlated, respectively. The analysis of precision and accuracy following solid-phase extraction met the requirements. (II) The C2h-DEFR of patients given 40 mg/kg were significantly higher than the ones from the other dosing groups (10 mg/kg, 25 mg/kg and 30 mg/kg) (p< 0.05). Drug concentrations normalized by body weight (C/D) were expressed as detected concentrations divided by daily DEFR (mg). Mean C2h/D(DEFR+Fe–[DEFR]2) of all patients (n=23) was 22.37 ± 14.28 μmole/L/g (4.91~56.92) suggesting intra-individual variations. However, C2h-DEFR, C2h-Fe–[DEFR]2 and C2h-DEFR+C2h-Fe–[DEFR]2 were significantly correlated with their daily dose (p< 0.05), respectively. Mean Ctrough/D(DEFR+Fe–[DEFR]2) of patients with completed drug utilization records (n=10) was 12.30 ± 10.04 μmole/L/g (3.59~31.68). The least ratio of Ctrough/D(DEFR+Fe–[DEFR]2) and C2h/D(DEFR+Fe–[DEFR]2) of the patients whose SF value below 1000 μg/L (n=4) divided by the withdrawal time was 0.02 μmole/L/g/h among the patients. Conclusion: Currently established analysis system of DEFR and Fe-[DEFR]2 applied for TDM in patients with β-thalassemia major can be utilized to clarify DEFR-related problems. Further studies are warranted to determine the minimum required drug concentrations to obtain effective therapeutic outcomes of DEFR in iron overlaod management.

並列關鍵字

deferasirox ； therapeutic drug monitoring ； β-thalassemia ； intra-individual variations

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