以藥物動力學探討地拉羅司控制鐵質沉積與長期療效預測指標

Taipei Medical University Institutional Repository > 藥學院 > 藥學系 > 博碩士論文 > Item 987654321/57973

請使用永久網址來引用或連結此文件: http://libir.tmu.edu.tw/handle/987654321/57973

題名:	以藥物動力學探討地拉羅司控制鐵質沉積與長期療效預測指標 Indicator for Prediction of Iron Deposition Control and Long-term Response to Deferasirox: A Pharmacokinetic Study
作者:	王寧 Wang, Ning
貢獻者:	藥學系(碩博士班) 吳姿樺
關鍵詞:	海洋性貧血;分次服用;地拉羅司;地拉羅司鐵螯合物;藥物動力學 thalassemia;twice-daily;deferasirox;deferasirox iron(III);pharmacokinetic
日期:	2014-07-18
上傳時間:	2019-09-09 10:44:07 (UTC+8)
摘要:	重度海洋性貧血患者需要終生定期的接受輸血的治療而導致病患體內鐵質過度負荷，因而需要接受適當的鐵螯合治療。地拉羅司 (deferasirox，DEFR) 為每日一次 (QD) 的口服鐵螯合劑，過去研究指出每日兩次(BID)的服用方法可改善部分病患療效不彰或減少藥物的副作用，但長期來看分次服用的鐵沉積控制成效仍不明確; 又分次服用對DEFR患者全身藥物暴露量是否有影響亦不清楚。此外，有研究指出DEFR在移除心臟鐵的能力較差，且海洋性貧血患者可能因肝臟鐵質沉積而影響胺基酸代謝，而患者生長遲緩亦被認為與鐵螯合藥物所而導致的鋅離子缺乏有關。因此本研究主要目的長期追蹤比較鐵控制成效並利用臨床藥事服務進行之療劑監測DEFR及Fe-[DEFR]2血中濃度(CDEFR，CFe-[DEFR]2)來建立藥物反應指標以預測長期控制療效，並建立病患完整的藥物動力學 (Pharmacokinetic，PK)，了解DEFR服用頻次與PK參數的關係。研究方法:追蹤先期試驗所收錄病患QD及BID服用DEFR長期之血清儲鐵蛋白 (serum ferritin，SF)及MRI心臟T2的數值，並藉由藥物血中濃度計算服藥後2小時螯合比 (CFe-[DEFR]2/CDEFR+ Fe-[DEFR]2) 分群探討鐵沉積控制追蹤成效，並檢測兩群病患其血清胺基酸含量是否有差異。PK試驗方面，共收錄8位病患，利用高效液相層析儀搭配紫外光檢測器之分析地拉羅司血中濃度(CDEFR)、地拉羅司鐵螯合物血中濃度 (CFe-[DEFR]2)。除了比較同位病患QD和BID的DEFR PK參數外，也探討依螯合比分群的病患其DEFR PK參數的差異及目前鐵沉積控制成效; 另外也收集病患24小時尿液檢測尿中鋅離子濃度。研究結果: 針對先期所收錄的QD (n = 18) 及BID (n = 10) 病患持續服用DEFR後平均經192.2~235.4日，追蹤鐵控制指標結果顯示QD vs. BID其SF平均改變值中位數(-112.0 vs. -25.0)及心臟T2平均改變值中位數 (+8.0 vs. +4.4) 皆有改善的趨勢, 但沒有明顯差異；依照螯合比分群，螯合比高於0.054的病患 (n = 10) 與螯合比低群組 (n = 18) 相較，SF平均經192.1日，T2平均經233日，追蹤鐵控制指標顯示其SF平均改變值中位數分別為-188.0 vs. +16.5，心臟T2平均改變值中位數分別為+10.1 vs. +4.5，顯示前者長期有較明顯的改善，且血清胺基酸含量L-serine及Glycine在兩組統計上有達到顯著的差異 (p < 0.05)。PK試驗方面，在BID服用時平均DEFR Ctrough/D與Cmax/D為91.3 ± 72.8、144.6 ± 72.9，皆大於QD服用42.3 ± 21.4、139.0 ± 59.8; 而QD vs. BID的平均AUC24分別為4290.2 ± 2365.6 vs. 5147.0 ± 3133.6，雖然BID AUC24較大但QD和BID各PK參數數值經統計分析後皆無顯著差異。病患依性別分組後，經劑量校正後之總藥物血中濃度顯示，相較於男性，女性不論在QD 和BID，平均Ctrough/D和Cmax/D皆較高。另外病患24小時尿液中鋅離子排泄量與DEFR Cmax具有顯著的相關性 (p < 0.05)。將本研究PK試驗所收錄病患追蹤鐵沉積療效，結果顯示高螯合比的病患目前SF平均值1379.3 ± 478.3 (n = 4)，較低螯合比病患2069.3 ± 2000.5控制鐵沉積療效較佳(n = 4)；但兩群組PK各參數皆無顯著差異。結論: 追蹤QD和BID病患鐵控制指標結果顯示皆有改善的趨勢; 但沒有明顯的差異，但BID服用DEFR並不會明顯改變藥物總暴露量。高螯合比的病患長期SF和心臟T2改善較多並有控制較穩定的趨勢，且在PK試驗具高螯合比的病患目前控制鐵沉積療效較佳。而螯合比高者能預測追蹤病患療效；未來臨床上可用來預測病患DEFR療效反應，但仍須進一步驗證並留意海洋性貧血病患可能有胺基酸及鋅離子缺乏的問題。 β-thalassemia major is an autosomal recessive hereditary anemia. Lifelong regular transfusions are necessary in these patients, and appropriate iron chelation therapy is needed to prevent iron overload resulting from frequent blood transfusions. Deferasirox (DEFR) is an oral iron chelator for once-daily (QD) use with unsatisfactory effect on removing cardiac iron. DEFR dosing by twice-daily (BID) was report to improve iron overload or decrease DEFR-related adverse effects, while it remains unclear whether BID use of DEFR has a long-term efficacy for iron deposition control better than QD use, or changes systemic drug exposure. Since iron deposition may cause changes in hepatic metabolism of amino acid and iron chelators may reported to cause growth retardation resulting from zinc deficiency. This study aimed to develop a useful drug level indicator for therapeutic drug monitor to follow up patients’ long-term DEFR’s responses and establish patients’ pharmacokinetic (PK) profiles dosing by QD or BID. Methods: Total twenty-eight patient’s serum ferritin (SF) level and cardiac T2 value by magnetic resonance imaging were follow up in patients treated with DEFR QD or BID use in our pilot study. Individual’s chelation ratio (CFe-[DEFR]2/CDEFR+Fe-[DEFR]2) at post-dose 2 hr was calculated serum amino acid levels were determined. Concentrations of DEFR (CDEFR) and Fe-[DEFR]2 (CFe-[DEFR]2) were analyzed by a validated HPLC-UV system. PK parameters and 24-hour urine zinc levels of recruited patients (n=8) subgrouped by different dosing regimen (QD vs. BID) or chelation ratio (high vs. low) were analyzed. Results: Long-term follow –up iron controls of patients with DEFR QD (n=18) vs. BID (n=10) for 192.2~235.4- day resulted in improvement in SF (median= -110.6 vs. -25.0) and cardiac T2* (median= +8 vs. +4), but there is no difference. The patients with chelation ratios higher than 0.054 (n=10) showed a favorable change in SF (median = -188.0 vs. +16.5) and cardiac T2* (+10.1 vs. +4.5) as compared to those with low chelation ratios (n=18) after the 192.1-day and 233.0 follow-up, respectively, for SF and T2, and had a significantly higher serum levels of L-serine and lower L-glycine than normal subject. In the PK study, mean DEFR Ctrough/D (91.3 ± 72.8 vs. 42.3 ± 21.4), mean Cmax/D (144.6 ± 72.9 vs. 139.0 ± 59.8), and AUC24 (5147.0 ± 3133.6 vs. 4290.2 ± 2365.6) were all higher in patients treated with DEFR BID compared to those with QD; however, there was no significant difference in all PK parameters. There is a correlation of 24-hour urine zinc excretion with DEFR Cmax (p<0.05). Compared with males, females had higher DEFR Ctrough/D and DEFR Ctrough/D regardless of the frequency of administration. Patients with a high chelation ratio (n=4) had an appreciable SF value 1379.3 ± 478.3, in comparison with 2069.3 ± 2000.5 in those with a low chelation ratio (n=4), but there was no statistically significant difference in PK parameters between the two groups. Conclusion: Patients treated with DEFR either by QD or BID had an improvement in iron control; however, there is no significant difference and DEFR dosing by BID did not significantly increase drug systemic exposure compared to QD regimen. The patients with high chelation ratios had a favorable effect on long-term control of SF, cardiac T2, and iron deposition. Notably, the deficiency of L-glycine should be monitored in low chelation ratios patients. Better iron control response to DEFR was observed in the patients with high chelation ratios. Chelation ratios might be applied as indicator to predict patients’ therapeutic efficacy clinically and, further confirm in larger population is warranted.
描述:	碩士指導教授-吳姿樺委員-郭代璜委員-許光陽
資料類型:	thesis
顯示於類別:	[藥學系] 博碩士論文

文件中的檔案:

檔案	描述	大小	格式	瀏覽次數
index.html		0Kb	HTML	53	檢視/開啟

檢視Licence

在TMUIR中所有的資料項目都受到原著作權保護.

TAIR相關文章

資料載入中.....