分次服用地拉羅司對重度海洋性貧血病患療劑監測成效之影響

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。地拉羅司 (deferasirox，DEFR) 為口服的鐵螯合劑，過去研究指出每日兩次 (BID) 的服用方法能改善部份病患療效不彰或減少藥物相關副作用。本研究旨在利用回溯性資料分析重度海洋性貧血患者在更動為BID用藥其療效及安全性改善情形；續而應用所建立之DEFR及其鐵螯合物（Fe-[DEFR]2）分析方法於穩態療劑監測與藥事服務。研究方法：本研究首先收錄BID服用DEFR持續五個月以上的病患，回溯分析其血清儲鐵蛋白 (serum ferritin，SF)、血清肌胺酸酐 (serum creatinine，Scr) 以及血清丙胺酸轉胺酶 (alanine aminotransferase，ALT)；繼而進行前瞻性研究，所收錄之病患需完成一週用藥紀錄表以確認其服藥順從性，利用高效液相層析儀搭配紫外光檢測器之系統分析BID服用DEFR的病患其服藥前與服藥後2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)；再以Pearson correlation統計分析劑量與藥物血中濃度 (CDEFR、CFe-[DEFR]2、CDEFR＋Fe-[DEFR]2)之相關性；進一步以療劑監測日三個月前之SF檢查值為100%，分別計算療劑監測日及前兩個月的SF檢查值平均異動百分比將病患區分adequate、stable、inadequat三組，以探討經劑量校正後之藥物血中濃度 (C/D比值)、平均螯合比與療效之關係。研究結果：回溯分析轉換為BID持續服用三個月後病患 (n = 10) 平均SF檢查值為2496.80 ± 1000.34，而再繼續於前瞻性研究收案當日追蹤其SF檢查值平均下降至1545.40 ± 1051.24 μg/L，兩者皆較QD期間最後檢查值顯著下降 (p < 0.05)；且能改善兩位病患因服用藥物引起之Scr檢查值上升以及關節痛。本研究所建立之 DEFR、Fe-[DEFR]2 之藥物分析系統符合確效標準，最低定量濃度則為5.36與0.63 μmole/L。前瞻性研究共收錄13位病患 (平均年齡23.10 ± 4.86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)。所有病患 (n = 13) 服藥前、服藥後2小時之總藥物 (DEFR＋Fe-[DEFR]2) 平均C/D比值分別為77.60 ± 55.28 μmole/L/g (6.58~197.08)、113.28 ± 49.93 μmole/L/g (39.49~218.56)。服藥前平均螯合比在各組 (adequate、stable、inadequate) 的數值分別為2.79 ± 0.64% (n = 2)、8.05 ± 2.82% (n = 6)、4.66 ± 1.71% (n = 2)。結論：BID服用方法能改善部份療效不彰或減少藥物相關副作用，且長期BID服用DEFR對肝腎功能是安全的；本研究所建立之藥物分析方法可應用於臨床療劑監測每日服用兩次DEFR之重度海洋性貧血患者，服藥後2小時之CDEFR或 CDEFR＋Fe-[DEFR]2與劑量有顯著關聯性；而其中SF檢查值控制相對穩定之病患，其服藥前DEFR鐵螯合物之劑量校正後之藥物血中濃度相對於體內藥物量來看是較其他病患組高，此項藥物動力學特性是否能提供做為臨床選用藥物及給藥頻次之參考，未來仍需進一步研究。

關鍵字

海洋性貧血；每日兩次；地拉羅司；地拉羅司鐵螯合物；療劑監測

並列摘要

β-thalassemia major is a hereditary anemic disease and lifelong transfusion is required for the patients. Appropriate iron chelation therapy is essential for reducing the risk of complications due to iron overload development. Deferasirox (DEFR) administered twice-daily is reported to improve iron overload or decrease DEFR-related adeverse effects (AEs) for some inadequate patients. Current study aimed to retrospectively evaluate the efficacy and safety outcomes in thalassemia major patients alternated to twice-daily DEFR and also establish an analytical system for therapeutic drug monitoring (TDM) of DEFR and deferasirox iron(Ⅲ) complex (Fe-[DEFR]2) in thalassemia major patients. Methods: (I) Patients treated with DEFR twice-daily for at least 5 months were retrospectively recruited and changes of serum ferritin (SF), serum creatinine (Scr) and alanine aminotransferase (ALT) were compared. (II) 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 under twice-daily dosing regimen. Patients were requested to document the compliance of DEFR prior to the day of blood collections (TDM day). The 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 dose-concentration relationship. Moreover, serum concentrations normalized by total daily dose (C/D ratio) or mean chelation ratio (CFe-[DEFR]2/ CDEFR+ Fe-[DEFR]2) were calculated. Patients were subgrouped into adequate (decreased more than 20%), stable (changes within ± 20%) and inadequate (increased more than 20%) according to their past three months SF values prior to the TDM day when compared to the earliest values of these four values. Result: Ten patients were recruited retrospectively and their mean SF values after switching to DEFR twice-daily for 3 months (2496.80 ± 1000.34 μg/L), or at prospective trial starting day (1545.40 ± 1051.24 μg/L) were analyzed and were significant decreased when compared to the one obtained on the last months of once-daily treatments (p < 0.05). DEFR-related Scr elevation and arthralgia occurred in 2 patients were improved. The analytical methodology was validated for standards of DEFR and Fe-[DEFR]2. Lower limit of quantitation were 5.36 and 0.63 μmole/L. In perspective study, the CDEFR and CDEFR＋Fe-[DEFR]2 of total recruited patients (n=13) at 2-hour post-dose were significantly correlated with doses in mg per kg (p < 0.05). Among all patients (n=13), mean C/D ratios of DEFR+Fe-[DEFR]2 at trough and 2-hour post-dose were 77.60 ± 55.28 μmole/L/g (6.58~197.08) and 113.28 ± 49.93 μmole/L/g (39.49~218.56), respectively. Mean chelation ratios of adequate, stable, inadequate groups at trough were 2.79 ± 0.64% (n=2)、8.05 ± 2.82% (n=6)、4.66 ± 1.71% (n=2). Conclusion: A twice-daily DEFR regimen improves efficacy or decrease DEFR-related AEs. Hepatic/renal lab data is within normal ranges after long term medication. The established analytical system for DEFR and Fe-[DEFR]2 can be applied for TDM 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; particularly, the mean trough concentration of DEFR-Fe complex normalized by doses in patients whose SF is stably controlled is higher than other groups. Further studies are still warranted to use this characteristics for appropriate medication selection and dosing regimen.

並列關鍵字

thalassemia ； twice-daily ； deferasirox ； deferasirox iron(Ⅲ) complex ； therapeutic drug monitoring

參考文獻

1. Modell B, Darlison M. Global epidemiology of haemoglobin disorders and derived service indicators. Bull World Health Organ 2008;86:480-7.

2. Vichinsky EP. Changing Patterns of Thalassemia Worldwide. Annals of the New York Academy of Sciences 2005;1054:18-24.

3. Cooley T, Lee P. A series of cases of splenomegaly in children with anemia and peculiar bone changes. Trans Am Pediatr Soc 1925;37:29-30.

4. Vento S, Cainelli F, Cesario F. Infections and thalassaemia. The Lancet Infectious Diseases 2006;6:226-33.

6. Cappellini, MD, ed. Guideline for the Clinical Management of Thalassemia Thalassaemia International Federation; 2008.

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分次服用地拉羅司對重度海洋性貧血病患療劑監測成效之影響

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