CYP2C19基因多型性與Voriconazole藥品血中濃度與不良反應之關聯性研究

CYP2C19 Genetic Polymorphisms in Relation to Voriconazole Concentration and Adverse Drug Reactions

賀筠婷(Yun-Ting He)

指導教授 ： 林淑文

共同指導教授 ： 沈麗娟

國立臺灣大學/醫學院/臨床藥學研究所/碩士(2012年)

https://doi.org/10.6342/NTU.2012.03269

摘要

背景：
Voriconazole為第二代廣效型抗黴菌藥品，為治療侵入性麴菌感染（Invasive aspergillosis）的一線用藥，具有飽和型非線性代謝的特性，主要經由肝臟酵素代謝，其中又以CYP2C19扮演最重要的角色。CYP2C19具有基因多型性，亞洲約有8.00 %~23.10 %為慢代謝者（poor metabolizer, PMs），不同的基因型使藥品血中濃度在個體間變異性大，PM的藥品血中濃度約是快代謝者（extensive metabolizer, EMs）的4~5倍，增加濃度相關的不良反應（adverse drug reaction, ADR）如肝毒性、幻覺與視覺干擾發生的風險。目前尚未有研究針對臺灣病人族群使用voriconazole時，不同CYP2C19基因型對藥品濃度或ADR造成的影響，因此本研究採前瞻性收案，研究不同CYP2C19基因型與voriconazole藥品濃度及ADR的相關性。
研究目的：
研究CYP2C19基因多型性與voriconazole血中濃度及與濃度相關ADRs間的相關性。
研究方法：
於2009年3月1日至2011年1月31日間，在臺大醫院與和信治癌醫院前瞻性收案門診或住院使用voriconazole的病人，病人了解並簽署同意書後納入研究分析。排除在進入研究前做過異體骨髓移植、CYP2C19基因型資料有缺漏、無藥品血中濃度或完全沒有穩定狀態藥品血中濃度、併用第一級顯著交互作用的藥品、治療過程中非使用一天兩次（BID或Q12H）的給藥模式之病人。
病人使用voriconazole 5~7天後達到穩定藥品血中濃度，即追蹤藥品谷濃度（trough concentration, Ctrough）及峰濃度（peak concentration, Cpeak）。使用高效能液相層析系統（HPLC）以UV偵測吸收波長來測定藥品濃度，並將自白血球中分離出的染色體，送至中央研究院國家基因體醫學研究中心進行iPLEX（Increased Plexing, Efficiency and Flexibility for MassARRAY System）基因型測定。
本研究紀錄收案病人基本資料、實驗室檢查值並觀察用藥期間是否有發生藥品不良反應（ADR），藥品不良反應以Naranjo scale評估與藥品的相關性，肝毒性方面另多用RUCAM scale評估，以評估判定確定（definite）、極有可能（highly probable）、極可能（probable）者為voriconazole相關ADR並納入分析。
統計方法使用Student’s t test、Mann-Whitney U test、χ2 test比較兩組樣本間的差異，使用Wilcoxon signed-rank test 比較三組樣本間的差異。以多元迴歸模式評估CYP2C19是否為影響藥品濃度的重要因子。
研究結果：
本研究收案127人，排除44位病人，一共83人納入分析，以血液腫瘤疾病為主（79.50 %），主要用來治療侵入性黴菌感染。83位病人中有31位（37.40 %）快代謝者（EM）、42位（50.60 %）中速代謝者（HEM）以及10位（12.00 %）慢代謝者（PM）。
為比較相同起始給藥頻次下，不同CYP2C19基因型的病人第一次測得voriconazole血中濃度的差別，在分析濃度與CYP2C19的相關性時，只分析75位使用一天兩次劑量且有第一次穩定狀態血中濃度的病人。本研究的Cpeak與Ctrough有很好的相關性（R2=0.91）。75位病人中有29位（38.70 %）EM、36位（48.00 %）HEM及10位（13.30 %）PM，CYP2C19基因型和藥品血中濃度沒有相關性。將病人依voriconazole使用途徑分組，75位中有49位（65.30 %）病人使用口服voriconazole，CYP2C19基因型會影響藥品濃度，其中HEM（3.87±2.41 mg/L）與PM（5.69±2.90 mg/L）的Ctrough顯著大於EM（2.51±2.04 mg/L）， HEM的藥品濃度約為EM的1.54倍，PM約為EM的2.30倍，p-value分別為0.05與0.03；以dose-adjusted Ctrough 也看到相同結果（p-value分別為0.03與0.04）。75位病人中有26位（34.60 %）使用靜脈注射劑型的病人，在這群病人中則看不出血中濃度的趨勢，PM病人甚至有較低的血中濃度，可能跟樣本數較少有關（N=26）。在濃度與CYP2C19基因型的迴歸分析中，發現口服病人群中，年齡與CYP2C19基因型可以預測25.70 %藥品濃度的變化。
本研究83位病人一共發生76件voriconazole相關ADR，其中最常見者為視覺干擾（42.10 %），其次為肝毒性（39.50 %）及幻覺（18.40 %）。CYP2C19基因型和任一ADR的發生沒有相關性，PM病人相較於HEM與EM病人有較高voriconazole相關ADR發生的趨勢。在肝毒性方面，CYP2C19基因型與voriconazole相關肝毒性的發生沒有顯著相關。在神經毒性如幻覺及視覺干擾方面，CYP2C19基因型和神經毒性的發生也沒有顯著相關。CYP2C19基因型和voriconazole相關ADR間沒有顯著相關，可能和本研究在追蹤病人的過程中，積極為病人調整voriconazole血中濃度使其落在療劑範圍（therapeutic range）之內有關。
結論：
本研究為第一個在使用口服與靜脈注射劑型voriconazole的病人，比較CYP2C19基因型與voriconazole血中濃度及不良反應間關係的研究。對於使用口服voriconazole的病人，CYP2C19基因型的變異會影響藥品濃度的變化，HEM與PM病人的平均Ctrough各約為EM病人的1.54及2.30倍，統計上有顯著差異。CYP2C19基因型的變異與不良反應的發生均沒有統計上顯著差異。

關鍵字

voriconazole ； CYP2C19 ； 血中濃度 ； 肝毒性 ； 幻覺 ； 視覺干擾

並列摘要

Background：
Voriconazole is a second-generation broad-spectrum antifungal agent. It is used as the first line treatment for invasive aspergillosis. Voriconazole exhibit saturable nonliniear pharmacokinetics. It is metabolized by liver enzymes, mainly CYP2C19. CYP2C19 has genetic polymorphism. There are 8.00 % to 23.10 % poor metabolizers (PMs) in Asian population. Voriconazole blood concentration has large intraindividual and interindividual variation. It is reported that PMs have 4 to 5 times higher trough voriconazole concentration than extensive metabolizers (EMs) do, thus they may experience increased risk of concentration-dependent toxicity, such as liver toxicity, hallucination and visual disturbance. There are limited data of voriconazole trough concentration and adverse drug reactions (ADRs) in relation to CYP2C19 genetic polymorphism in Taiwan, therefore we performed a prospective study to investigate CYP2C19 genetic polymorphism and its relationship to voriconazole concentration and voriconazole-associated ADRs.
Objective：
CYP2C19 genetic polymorphism in relation to voriconazole concentration and concentration-dependent ADRs.
Methods：
This prospective study was held in National Taiwan University and Koo Foundation Sun Yat-Sen Cancer Center from March 1st in 2009 to Janurary 31st in 2011. Inpatients and outpatients who used voriconazole and signed the informed consent were included in this study. Patients who have had allogeneitic bone marrow transplantation prior to enrollment, did not have CYP2C19 genetic information, did not have voriconazole concentration or did not have steady state voriconazole concentration, co-administered significance rating 1 drug interaction drugs while testing voriconazole concentration, did not use twice daily(BID or Q12H) regimen were excluded.
Steady state voriconazole plasma concentration (peak and trough) were drawn 5-7 days after initiating voriconazole. Voriconazole concentration were determined by high performance liquid chromatography and UV light. DNA samples were extracted from the patients’ white blood cell. iPLEX (Increased Plexing, Efficiency and Flexibility for MassARRAY System) was performed to dectect for genetic polymorphism.
Patients’ demographic character, lab results and vori-associated ADRs were recorded. The Narajo scale was applied to evaluate the causality of the ADRs in relation to voriconazole use. In addition, RUCAM scale was applied to evaluate drug associated hepatotoxicity. Voriconazole associated ADRs were ADRs which were evaluated as “Definite”, “probable” in Naranjo scale or “highly probable”, “probable” in RUCAM scale. Voriconazole associated ADRs will be analysed for the relationship between CYP2C19 genetic polymorphism and ADRs.
Student’s t test, Mann-Whitney U test, and χ2 test were used to compare the differences between two groups. Wilcoxon signed-rank test was used to compare the differences among three groups. Multiple regression was used to investigate whether CYP2C19 genetic polymorphism is a main factor for predicting voriconazole plasma concentration.
Results：
A total of 127 patients were enrolled, but only 83 patients were included in the analysis. Most of them had hematological disease (79.50 %). Voriconazole was used for invasive fungal infections. Thirty one patients (37.40 %) were CYP2C19 EMs, 42 patients (50.60 %) were CYP2C19 heterozygous extensive metabolizers (HEMs) and 10 patients (12.00 %) were CYP2C19 PMs in the patient population.
In the study of CYP2C19 polymorphism in relation to voriconazole concentration, only the first steadt state voriconazole concentration was included for comparing the voriconazole concentration under same initial dosing frequency. There were 75 patients meeting the criteria. There was a good correlation between trough concentrations and peak concentrations in this study. Among total 75 patients, there were 29 (65.30%) EMs, 36 (48.00%) HEMs and 10 (13.30%) PMs. There was not a correlation between CYP2C19 polymorphism and voriconazole concentration. There were 49 (65.30 %) patients took oral form voriconazole, the polymorphism of CYP2C19 made correlate significantly with variation of voriconazole plasma concentrations. HEMs (3.87 ± 2.41 mg/L) and PMs (5.69 ± 2.90 mg/L) had higher trough concentrations than EMs (2.51 ± 2.04 mg/L), with p-values of 0.05 and 0.03, respectively. If dose-adjusted trough was used instead, similar results were found, with p-values of 0.03 and 0.04, respectively. Twenty-six patients received intraveneous (IV) form of voriconazole. There was no relationship between trough (dose-adjusted trough) and CYP2C19 polymorphism in patients who use IV form of voriconazole. PMs had unexpected lower drug concentrations compared to EMs and HEMs. This result may be due to small sample size of patients who used IV form of voriconazole (N=26). In the multiple regression model, age and CYP2C19 polymorphism can predict 25.70% of the change of voriconazole trough concentration in patients who were on oral form of voriconazole.
There were 76 voriconazole associated (vori-associated) ADRs in 83 patients. The most common ADRs of voriconaozle are visual disturbance (42.10 %), hallucination (18.40 %) and hepatotoxicity (39.50 %). There was no correlation between CYP2C19 polymorphism and vori-associated ADRs, however PM patients seemed to have higher ratio of vori-associated ADRs. Take a deep look to each vori-associated ADRs. There was no correlation between CYP2C19 polymorphism and vori-associated hepatotoxicity、vori-associated hallucination and vori-associated visual disturbance respectively.
Conclusion：
In patients who used oral form voriconazole, voriconazole trough concentrations of HEMs and PMs were 1.54 and 2.30 times higher than Ems, respectively. PMs had higher risk of having voriconazole associated ADRs. However, there was no correlation between CYP2C19 and vori-associated ADRs.

並列關鍵字

voriconazole ； CYP2C19 ； voriconazole concentration ； hepatotoxicity ； hallucination ； visual disturbance

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