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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 林淑文 | |
dc.contributor.author | Hon-Ying Tsai | en |
dc.contributor.author | 蔡弘穎 | zh_TW |
dc.date.accessioned | 2021-05-16T16:18:34Z | - |
dc.date.available | 2018-09-24 | |
dc.date.available | 2021-05-16T16:18:34Z | - |
dc.date.copyright | 2013-09-24 | |
dc.date.issued | 2013 | |
dc.date.submitted | 2013-08-14 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/5939 | - |
dc.description.abstract | 背景
黴菌感染主要發生在免疫不全病人,會造成嚴重的共病(morbidity)與死亡率(mortality)。廣效性抗黴菌藥物posaconazole在黴菌感染的預防及治療都有重要的角色。Posaconazole血中濃度越高療效反應越好,越來越多文獻提出監測posaconazole血中濃度的重要性。但臨床觀察posaconazole血中濃度有極高的個體間(inter-individual)和個體內(intra-individual)差異,亦受飲食、腸胃道功能、腸胃用藥等影響。之前研究未有posaconazole與P-glycoprotein(MDR1)SNPs 1236 C>T,2677 G>T/A,3435 C>T/A 和haplotype的相關研究,更缺乏亞洲族群使用posaconazole的相關研究,目前也沒有研究探討此藥物代謝酵素UGT1A4基因多重性的影響。 研究目的 分析posaconazole處方型態,探討posaconazole濃度和臨床反應、藥品不良反應的關係,並分析可能影響posaconazole濃度的因子。最後評估本院是否需要例行監測posaconazole血中濃度。 研究方法 本研究於2012年11月1日至2013年5月31日間,在國立臺灣大學附設醫院前瞻性收案使用posaconazole的病人。經病人簽署受試者同意書後,於服藥7-10天穩定狀態後進行療劑監測,測量儀器為HPLC和UV偵測吸收波長,並以PCR-RFLP分析酵素基因多型性。本研究將療劑監測結果報告給醫療團隊,並提供劑量調整、藥物交互作用建議處置等藥事服務。 記錄用藥期間病人基本資料、生化檢驗值、posaconazole處方型態、病人腸胃道功能及飲食狀況、藥品交互作用,並觀察是否出現相關不良反應。臨床反應部分,由感染科醫師就用藥結束時或研究觀察終點時,評估posaconazole之預防或治療反應。 統計方法以χ2 test、Fisher exact test、Mann-Whitney U Test檢定兩組差異,以simple linear regression、multiple linear regressionwith and without GEE model與logistic regression分析posaconazole濃度,與各種危險、預後因子的影響力。 研究結果 本研究總收案人數42人,有效樣本共41位,包含23位預防性及18位治療性使用。 預防性使用部分,共 33件預防事件(化學治療27件,移植後植體宿主反應組6件),年齡中位數為43(22-72)歲,65.2%為女性。18位治療性使用posaconazole病人中,年齡中位數為53.5(27-87)歲,一半為女性,13位 (72.2)%有潛在血液疾病,適應症以可能感染(44.4%)和確定感染(38.9%)為主,用藥原因以前線治療失敗或出現副作用(55.6%)居多。 研究期間共有103筆濃度資料,預防性使用53筆,中位數為643 ng/mL (137-2397),達到文獻建議目標比例為43.4%;治療性使用50筆,中位數為711.5 ng/mL (0-3223),目標達成率22%。另外,同一病人的濃度變化可達0.9-10.7倍。 臨床反應部分,預防性使用的失敗率為15.2%,經感染科醫師判斷,侵入性黴菌感率為9.1%。預防失敗組posaconazole濃度目標達成率為0%,且顯著較成功組低。但在納入其他預後因子分析後,posaconazole濃度無顯著意義。治療性使用posaconazole的成功率為50%,但濃度在成功、失敗組的分佈無顯著差異。 和posaconazole使用相關之不良反應有ALT上升(11.8%)、AST上升(3.9%)、低血鉀(7.8%),和posaconazole血中濃度無明顯相關。 年紀、腹瀉、併用PPI、併用酵素誘導劑會顯著降低posaconazole濃度,增加攝食量則和濃度上升相關。MDR1 2677G>T/A基因多型性和濃度分佈有顯著關係,其他基因多型性則無顯影響。 結論 本研究中posaconazole血中濃度越高,預防黴菌感染效果越好。血中濃度和治療效果的關係則無顯著意義。Posaconazole濃度在個體內及個體間差異性大,年紀、腸胃道功能、併用藥品和攝食量扮演重要角色,因此posaconazole血中濃度監測在預防性使用,或病人腸胃道功能變化大時有其必要性。 關鍵字 Posaconazole、療劑監測、posaconazole血中濃度、侵入性黴菌感染、單核苷酸多型性(single nucleotide polymorphism,SNP) | zh_TW |
dc.description.abstract | Background
Invasive fungal infection (IFI) may cause high mortality and morbidity in immune- compromised patients. Posaconazole, a new triazole antifungal agent with broad spectrum coverage, was approved for both treatment and prophylaxis of IFIs. Previous studies have demonstrated the relationship between posaconazole plasma concentration and efficacy, thus, the importance of posaconazole therapeutic drug monitoring (TDM) was gradually accepted. However, studies found inter- and intra-individual variation between concentrations, and these phenomenons were affected greatly by GI function, food intake and concomitant medication. Besides, the role of p-glycoprotein MDR1 SNP 1236 C>T,2677 G>T/A,3435 C>T/A and haplotype, and UGT1A4 genotype are less studied. Furthermore, there’s a lack of posaconazole TDM study in Asian population. Objectives The study was designed to describe the prescribing pattern of posaconazole, to study the relationship between concentration and clinical outcomes/ adverse events, to identify factors that influence plasma concentration, and to evaluate whether routine TDM is needed in our institution. Methods This prospective study was conducted at National Taiwan University Hospital between November 2012 and May 2013, and informed consents were signed before enrollment. After 7-10 days of taking posaconazole, steady state concentration was measured by HPLC and UV detector, and PCR-RFLP was performed to detect genetic polymorphism. The results of posaconazole TDM were reported to the primary care team, and we also provided recommendation about dosage adjustment and drug interaction. Baseline characteristics, lab data, prescribing patterns, GI function, food intake and drug interaction were collected, and adverse effects were recorded during study period. Clinical responses were evaluated by infectious disease specialists at the time of posaconazole discontinuation or study end date, whichever occurred first. χ2 test, Fisher exact test and Mann-Whitney U Test were used to compare the difference between groups; simple linear regression, multiple linear regression and multiple logistic regression were performed to study the impact of posaconazole concentration on clinical outcomes. Results A total of 41 patients with TDM results were enrolled, including 23 prophylaxis and 18 treatment use. There were 33 prophylaxis events (27 events for chemotherapy, 6 events for graft-versus-host disease). The median age was 43 years old (22-72), and 65.2% of the patients were females. As for the treatment group, the median age was 53.5 years old (27-87), 50% of the patients were females, 72.2% had hematologic underlying disease, and posaconazole was prescribed mostly for possible (44.4%) and proven (38.9) IFIs due to failure or intolerance of previous antifungal agents (55.6%). We collected 103 posaconazole concentrations, 53 in the prophylaxis and 50 in the treatment group. The median concentration was 643 ng/mL (137-2397) in the prophylaxis group, and 43.4% of the concentrations achieved the goal for prophylaxis. The median concentration was 711.5 ng/mL (0-3223) in the treatment groups, and only 22% reached the goal for treatment. Besides, concentration could be 0.9- 10.7 times different in an individual patient. Prophylaxis failure rate was 15.2% in this study, and breakthrough IFI developed in 9.1% of the prophylaxis events. None of the concentrations in failure group reached the goal, and concentrations were statistically lower compared with those of prophylaxis success, but there was no statistically significance when logistic regression was performed and other prognostic factors were considered. Treatment success rate was 50%. However, there was no statistical difference of concentrations between success and failure group. We indentified ALT elevation (11.8%), AST elevation (3.9%), hypokalemnia (7.8%) which were related to posaconazole use, and these adverse events were not associated with posaconazle exposure. Age, diarrhea, concomitant PPI or enzyme inducer use were associated with lower posaconazole concentration, whereas food intake was associated with concentration increase. We didn’t find the influence of UGT1A4, MDR1 genetic polymorphism and haplotype, but MDR1 2677G>T/A was associated with differences between concentrations. Conclusion We have found that higher posaconazole concentration was associated with success in IFI prophylaxis, but not with IFI treatment. There’s great inter and intra- individual variation between concentration, and age, GI function, concomitant medications as well as food intake affected most. Thus, there’s a need for posaconazole TDM in these circumstances. Keywords Posaconazole, therapeutic drug monitoring、posaconazole plasma concentration, single nucleotide polymorphism | en |
dc.description.provenance | Made available in DSpace on 2021-05-16T16:18:34Z (GMT). No. of bitstreams: 1 ntu-102-R00451003-1.pdf: 1997418 bytes, checksum: be83fb0b3b86d8b3848f23da8e071445 (MD5) Previous issue date: 2013 | en |
dc.description.tableofcontents | 中文摘要 iv
Abstract vii 目錄 xi 圖表目錄 xiii 第一章 緒論 1 第二章 文獻探討 2 2.1 侵入性黴菌感染 2 2.2 Posaconazole 簡介 3 2.3 療劑監測 11 2.4 預防性使用posaconazole 16 2.4 UGT1A4與P-glycoprotein基因多型性 17 第三章 研究目的 19 第四章 研究方法 20 4.1研究架構 20 4.2 研究對象、地點 20 4.3 納入及排除條件 21 4.4 資料收集 21 4.5 Posaconazole血中濃度測定方法 24 4.6 UGT 1A4、MDR1酵素基因多型性測定方法 24 4.7 適應症及臨床療效評估 27 4.8 不良反應評估 33 4.9 藥品交互作用評估 35 4.10其他影響臨床反應之危險因子與預後因子 38 4.11 統計方法 39 第五章 研究結果 40 5.1 收案情形 40 5.2病人基本資料 41 5.3 Posaconazole濃度與臨床反應分析 53 5.4 Posaconazole濃度與影響因子分析 59 5.5 Posaconazole濃度與不良反應分析 70 5.6藥品交互作用評估 74 5.7 療劑監測與藥事服務 76 第六章 討論 81 6.1 病人族群與適應症 81 6.2 Posaconazole濃度與臨床反應 82 6.3 Posaconazole濃度與影響因子 83 6.4 Posaconazole濃度與不良反應 87 6.5 療劑監測之臨床考量 87 6.6 研究限制 88 6.7 未來展望 89 第七章 結論 90 參考文獻 92 | |
dc.language.iso | zh-TW | |
dc.title | 某醫學中心Posaconazole之療劑監測 | zh_TW |
dc.title | Therapeutic Drug Monitoring of Posaconazole in a Medical Center | en |
dc.type | Thesis | |
dc.date.schoolyear | 101-2 | |
dc.description.degree | 碩士 | |
dc.contributor.coadvisor | 沈麗娟 | |
dc.contributor.oralexamcommittee | 陳宜君,李啟誠,蕭斐元 | |
dc.subject.keyword | Posaconazole,療劑監測,posaconazole血中濃度,侵入性黴菌感染,單核苷,酸多型性, | zh_TW |
dc.subject.keyword | Posaconazole,therapeutic drug monitoring,posaconazole plasma concentration,single nucleotide polymorphism, | en |
dc.relation.page | 99 | |
dc.rights.note | 同意授權(全球公開) | |
dc.date.accepted | 2013-08-14 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 臨床藥學研究所 | zh_TW |
顯示於系所單位: | 臨床藥學研究所 |
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