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類別 臨床試驗類,藥動學試驗基準,肝功能不全病患的藥動學試驗基準
法規性質 行政解釋
法規名稱 肝功能不全病患的藥動學試驗基準
條文內容 <div style="layout-grid: 18pt none;" class="WordSection1"><p style="text-align: center; line-height: 12pt;">&nbsp;</p><p style="text-align: center; line-height: 12pt;">&nbsp;</p><p style="text-align: center; line-height: 12pt;">&nbsp;</p><p style="text-align: center; line-height: 12pt;">&nbsp;</p><p style="text-align: center; line-height: 12pt;">&nbsp;</p><p style="text-align: center;"><span style="font-family: 新細明體,serif; color: black; font-size: 20pt;">肝功能不全病患的藥動學試驗基準</span> </p><p style="text-align: center;"><span style="font-family: 新細明體,serif; color: black; font-size: 20pt;">－臨床試驗設計、數據分析以及對劑量調整與標示的影響</span> </p><p style="text-align: center; line-height: 12pt;">&nbsp;</p><h1 style="text-align: center;"><span style="color: black; font-size: 16pt; text-decoration: underline; text-underline: none;">GUIDANCE FOR PHARMACOKINETICS IN PATIENTS WITH IMPAIRED HEPATIC FUNCTION: STUDY DESIGN, DATA ANALYSIS, AND IMPACT ON DOSING AND LABELING</span></h1><p style="text-align: center;">&nbsp;</p><p style="text-align: center;"><span style="font-family: 新細明體,serif; font-size: 16pt;">行</span> <span style="font-family: 新細明體,serif; font-size: 16pt;">政</span> <span style="font-family: 新細明體,serif; font-size: 16pt;">院</span> <span style="font-family: 新細明體,serif; font-size: 16pt;">衛</span> <span style="font-family: 新細明體,serif; font-size: 16pt;">生</span> <span style="font-family: 新細明體,serif; font-size: 16pt;">署</span> </p><p style="text-align: center;"><span style="font-family: 新細明體,serif; font-size: 16pt;">中華民國九十年七月</span> </p></div><span style="font-family: times new roman,serif; font-size: 16pt;"><br style="page-break-before: always;" clear="all" /></span><div style="layout-grid: 18pt none;" class="WordSection2"><p style="text-align: center;"><span style="font-family: 新細明體,serif; color: black; font-size: 16pt;">目錄</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 150%;">&nbsp;</p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 150%;"><span style="line-height: 150%; font-family: 新細明體,serif; color: black; font-size: 14pt;">第一章、前言</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 150%;"><span style="line-height: 150%; font-family: 新細明體,serif; color: black; font-size: 14pt;">第二章、背景</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 150%;"><span style="line-height: 150%; font-family: 新細明體,serif; color: black; font-size: 14pt;">第三章、決定是否須於肝功能不全病患執行臨床試驗</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 150%;"><span style="line-height: 150%; font-family: 新細明體,serif; color: black; font-size: 14pt;">第四章、臨床試驗設計</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 150%;"><span style="line-height: 150%; font-family: 新細明體,serif; color: black; font-size: 14pt;">第五章、數據分析</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 150%;"><span style="line-height: 150%; font-family: 新細明體,serif; color: black; font-size: 14pt;">第六章、標示</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 150%;"><span style="line-height: 150%; font-family: 新細明體,serif; color: black; font-size: 14pt;">參考文獻</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 150%;"><span style="line-height: 150%; font-family: 新細明體,serif; color: black; font-size: 14pt;">附錄：肝功能的評估</span> </p><span style="font-family: times new roman,serif; color: black; font-size: 10pt;"><br style="page-break-before: always;" clear="all" /></span><p style="text-align: center; line-height: 12pt;"><b><span style="font-family: 新細明體,serif; color: black;">第一章、前言</span> </b></p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt; margin: 0cm 1.4pt 0pt 11.9pt;">&nbsp;</p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt; margin: 0cm 1.4pt 0pt 11.9pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">本基準的目的在協助試驗委託者執行評估肝功能不全對藥品藥動學</span><span style="color: black; font-size: 11pt;">(pharmacokinetics)</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">性質之影響的試驗</span><span style="font-family: 新細明體,serif; font-size: 11pt;">，並且依據試驗結果作適當的劑量調整與標示，<span style="color: black;">必要時也將評估肝功能不全對於藥品藥效學（</span></span><span style="color: black; font-size: 11pt;">pharmacodynamics</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）性質之影響。此外，針對此一特殊群體所做的試驗分析結果亦可作為銜接性試驗的考量因素之一。本基準的內容包含：</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt; margin: 0cm 1.4pt 0pt 48pt;"><span style="font-family: wingdings; color: black; font-size: 11pt;">n<span style="font: 7pt times new roman;">&nbsp;&nbsp; </span></span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">何時應執行藥品在肝功能不全病患的藥動學試驗</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt; margin: 0cm 1.4pt 0pt 48pt;"><span style="font-family: wingdings; color: black; font-size: 11pt;">n<span style="font: 7pt times new roman;">&nbsp;&nbsp; </span></span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">設計與執行藥品在肝功能不全病患的藥動學試驗</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt; margin: 0cm 1.4pt 0pt 48pt;"><span style="font-family: wingdings; color: black; font-size: 11pt;">n<span style="font: 7pt times new roman;">&nbsp;&nbsp; </span></span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">臨床試驗群體之特性</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt; margin: 0cm 1.4pt 0pt 48pt;"><span style="font-family: wingdings; color: black; font-size: 11pt;">n<span style="font: 7pt times new roman;">&nbsp;&nbsp; </span></span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">臨床試驗結果的分析、解釋及報告，以及如何在標示</span><span style="color: black; font-size: 11pt;">(labeling)</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">中描述這些結果</span> </p><p style="margin: 0cm 1.4pt 0pt 12pt;"><span style="font-family: 新細明體,serif; font-size: 11pt;">本基準並不提供如何評估藥品在治療肝臟疾病的安全性及有效性，也不提供如何評估藥品是否會引起肝毒性。</span> </p><span style="font-family: times new roman,serif; color: black; font-size: 11pt;"><br style="page-break-before: always;" clear="all" /></span><p style="text-align: center; line-height: 20pt;"><b><span style="font-family: 新細明體,serif; color: black;">第二章、背景</span> </b></p><p style="text-align: center; line-height: 20pt;"><b></b></p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">　</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">肝臟與許多藥品的清除（</span><span style="color: black; font-size: 11pt;">clearance</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）有關，它可經由不同的代謝途徑或經由膽汁排泄的途徑排除原藥品或其代謝物。肝功能不全所引起藥品排泄或代謝速率的改變，會造成藥品蓄積或阻礙藥品形成活性代謝物。</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;">&nbsp;</p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">　許多文獻顯示肝病會改變藥品的藥動學及藥效學性質。這些報告中的試驗對象是患有常見肝病的病患。我國常見之肝病包括慢性</span><span style="color: black; font-size: 11pt;">B</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">型或</span><span style="color: black; font-size: 11pt;">C</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">型肝炎或肝硬化、脂肪肝、急性</span><span style="color: black; font-size: 11pt;">A</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">型或</span><span style="color: black; font-size: 11pt;">D</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">型肝炎、酒精性肝病（</span><span style="color: black; font-size: 11pt;">alcoholic liver disease</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）以及原發型膽汁性肝硬化（</span><span style="color: black; font-size: 11pt;">primary biliary cirrhosis</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）。由於國情環境的差異，美國</span><span style="color: black; font-size: 11pt;">FDA</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">所列舉的常見肝病中的急性</span><span style="color: black; font-size: 11pt;">E</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">型肝炎、原發型硬化性膽道炎（</span><span style="color: black; font-size: 11pt;">primary sclerosing cholangitis</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）與</span><span style="font-family: symbol; color: black; font-size: 11pt;">a</span><sub><span style="color: black; font-size: 11pt;">1</span></sub><span style="color: black; font-size: 11pt;">-</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">抗胰蛋白酵素缺乏症（</span><span style="font-family: symbol; color: black; font-size: 11pt;">a</span><sub><span style="color: black; font-size: 11pt;">1</span></sub><span style="color: black; font-size: 11pt;">-antitrypsin deficiency</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）在國人則相當罕見，而急性</span><span style="color: black; font-size: 11pt;">D</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">型肝炎則是國人常見的一種肝病。肝病也可能會影響腎功能，以至於即使肝臟並非某些藥品的主要清除途徑，仍然會引起藥品及其代謝物的蓄積。肝病也會造成藥品藥效（</span><span style="color: black; font-size: 11pt;">PD effects</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）的改變，例如某些藥品會增加肝衰竭病患之肝腦病變。至於其他疾病對於肝功能的特定影響，尤其在評估對於藥品藥動及藥效的影響上，通常只被簡略的描述，而且其結論之差異性頗大。</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;">&nbsp;</p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">　對於主要經由腎臟排除的藥品，測量肌氨酸酐</span><span style="color: black; font-size: 11pt;">(creatinine)</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">或其清除率則常被用來調整此類藥品的劑量。同樣的，膽紅素（</span><span style="color: black; font-size: 11pt;">bilirubin</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）、白蛋白（</span><span style="color: black; font-size: 11pt;">albumin</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）、前凝血酵素時間（</span><span style="color: black; font-size: 11pt;">prothrombin time</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）、</span><span style="color: black; font-size: 11pt;">antipyrine</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">、</span><span style="color: black; font-size: 11pt;">indocyanine green</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">（</span><span style="color: black; font-size: 11pt;">ICG</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）、</span><span style="color: black; font-size: 11pt;">monoethylglycinexylidide</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">（</span><span style="color: black; font-size: 11pt;">MEGX</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）及半乳糖（</span><span style="color: black; font-size: 11pt;">galactose</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）等連續性變數也曾被用來測量肝功能。此外，類別性的臨床變數也曾被用來評估肝功能。這些臨床變數包括腹水（</span><span style="color: black; font-size: 11pt;">ascites</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）、腦病變（</span><span style="color: black; font-size: 11pt;">encephalopathy</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）、營養狀況、週邊水腫</span><span style="color: black; font-size: 11pt;">(peripheral edema)</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">、病理學上肝纖維化的程度，或是變數的組合，如</span><span style="color: black; font-size: 11pt;">Child-Pugh </span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">分類法用於對酒精性肝硬化</span><span style="color: black; font-size: 11pt;">(alcoholic cirrhosis) </span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">及門脈高血壓</span><span style="color: black; font-size: 11pt;">(portal hypertension)</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">、</span><span style="color: black; font-size: 11pt;">Mayo risk scores</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">用於對原發型膽汁性肝硬化（</span><span style="color: black; font-size: 11pt;">primary biliary cirrhosis</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）及原發型硬化性膽管炎</span><span style="color: black; font-size: 11pt;">(primary sclerosing cholangitis)</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">，以及</span><span style="color: black; font-size: 11pt;">Maddrey</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">－</span><span style="color: black; font-size: 11pt;">Carithers discriminant function</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">用於對急性酒精性肝炎（</span><span style="color: black; font-size: 11pt;">acute alcoholic hepatitis</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）等（詳見附錄：肝功能評估方法）。然而，即使有上述的努力，目前仍無任何一種方法，已在臨床上被廣泛用來預測肝功能不全對於藥品藥動學及藥效學性質的影響。</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;">&nbsp;</p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">雖然臨床上並無有效的肝功能測量方法被廣泛用來預測藥品的藥動學及藥效學性質，藥品於研發階段在肝功能不全病患上所執行的臨床試驗，仍足以提供有用的資訊來決定此藥品在肝功能不全病患的起始劑量。但使用這些資訊必得配合仔細觀察及劑量逐步調整（</span><span style="color: black; font-size: 11pt;">dose titration</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）以獲致個別病人之最佳使用劑量。</span> </p><span style="font-family: times new roman,serif; color: black; font-size: 11pt;"><br style="page-break-before: always;" clear="all" /></span><p style="text-align: center; line-height: 20pt;"><b><span style="font-family: 新細明體,serif; color: black;">第三章、決定是否須於肝功能不全病患執行臨床試驗</span> </b></p><h2 style="line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">一、何時可能須於肝功能不全病患執行臨床試驗</span> </h2><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">(</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">一</span><span style="color: black; font-size: 11pt;">)</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">當藥品或其活性代謝物顯著經由肝臟代謝或排泄，本基準建議於肝功能不全病患執行藥動學試驗。</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">(</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">二</span><span style="color: black; font-size: 11pt;">)</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">當藥品或其活性代謝物具有狹窄治療範圍（</span><span style="color: black; font-size: 11pt;">narrow therapeutic range</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）或可能用於腎衰竭病患時，肝臟代謝之途徑變得較為重要，即使其原來未顯著（</span><span style="color: black; font-size: 11pt;">&lt;20</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">﹪）經肝臟代謝或排除，本基準也建議於肝功能不全病患執行臨床試驗。</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">(</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">三</span><span style="color: black; font-size: 11pt;">)</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">當藥品的代謝不明，且缺乏其它資料顯示肝排除途徑之比例較低時<b>，</b>應考慮該藥可能會被肝臟顯著代謝。</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">(</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">四</span><span style="color: black; font-size: 11pt;">)</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">當肝病種類與藥品原開發國不同時，應考慮該藥品在肝臟之代謝可能會因而受到影響。</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;">&nbsp;</p><h2 style="line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">二、何時可能不須於肝功能不全病患執行臨床試驗</span> </h2><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">對於某些藥品，肝功能不全不太可能明顯改變其藥動學性質，而須調整劑量；在這些況下，此類臨床試驗可能有益於預測藥品性質但並非必要。下述藥品的性質可能有助於判斷：</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">(</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">一</span><span style="color: black; font-size: 11pt;">)</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">藥品完全經由腎臟排除且與肝臟無關。</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">(</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">二</span><span style="color: black; font-size: 11pt;">)</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">藥品只有少部份（＜</span><span style="color: black; font-size: 11pt;">20</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">﹪）被肝臟代謝，且其治療範圍很廣，因此肝功能不全並不會產生毒性或增加該藥與其他藥品間的交互作用。</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">(</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">三</span><span style="color: black; font-size: 11pt;">)</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">氣態或揮發性藥品，且該藥品及其活性代謝物主要經由肺臟排除。</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">(</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">四</span><span style="color: black; font-size: 11pt;">)</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">對於單次使用的藥品，除非有臨床上的考慮，也許不須以肝功能不全病患進行臨床試驗。</span> </p><span style="font-family: times new roman,serif; color: black; font-size: 11pt;"><br style="page-break-before: always;" clear="all" /></span><p style="text-align: center; line-height: 20pt;"><b><span style="font-family: 新細明體,serif; color: black;">第四章、臨床試驗設計</span> </b></p><p style="text-align: center; line-height: 20pt;"><b></b></p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">試驗設計的重點如下</span><span style="color: black; font-size: 11pt;">:</span></p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">一、簡式臨床試驗設計</span><span style="color: black; font-size: 11pt;">(Reduced Study Design)</span></p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">二、基本完整的臨床試驗設計</span><span style="color: black; font-size: 11pt;">(Basic Full Study Design)</span></p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">三、群體藥動處理方式</span><span style="color: black; font-size: 11pt;">(Population PK Approach)</span></p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;">&nbsp;</p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><b><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">一、簡式臨床試驗設計</span></b><b> </b></p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">（一）、受試者</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">FDA</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">在調查</span><span style="color: black; font-size: 11pt;">1995</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">至</span><span style="color: black; font-size: 11pt;">1998</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">年間為了新藥申請</span><span style="color: black; font-size: 11pt;"> (New Drug Applications, NDAs) </span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">所執行的</span><span style="color: black; font-size: 11pt;">57</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">個針對肝功能不全病患進行的藥動學研究時發現，其中的</span><span style="color: black; font-size: 11pt;">55% </span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">使用</span><span style="color: black; font-size: 11pt;">Child-Pugh</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">分類法來評估肝功能。在這</span><span style="color: black; font-size: 11pt;">57</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">個試驗中有</span><span style="color: black; font-size: 11pt;">19</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">個試驗包括藥品在各種受試者上的口服清除率；這些受試者包括具有正常肝功能及肝功能不全的病患（依</span><span style="color: black; font-size: 11pt;">Child-Pugh </span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">分類為輕度、中度及重度）。而這</span><span style="color: black; font-size: 11pt;">19</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">個試驗中的</span><span style="color: black; font-size: 11pt;">17</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">個試驗結果顯示口服藥品清除率與肝功能不全的嚴重程度呈負相關</span><span style="color: black; font-size: 11pt;"> (</span><span style="font-size: 11pt;">r<sup>2</sup> </span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">介於</span><span style="color: black; font-size: 11pt;">0.5 </span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">和</span><span style="color: black; font-size: 11pt;">1.0</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">之間</span><span style="color: black; font-size: 11pt;">)</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">。同時，這</span><span style="color: black; font-size: 11pt;">19</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">個試驗中的</span><span style="color: black; font-size: 11pt;">16</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">個試驗結果顯示在</span><span style="color: black; font-size: 11pt;">Child-Pugh</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">分類為中度肝功能不全的病患有肝臟代謝機能不全。</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;">&nbsp;</p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">就像使用血清肌氨酸酐的濃度或肌氨酸酐清除率來評估腎功能不全的程度一樣，我們建議用</span><span style="color: black; font-size: 11pt;">Child-Pugh</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">分類法來評估肝功能不全的程度。這就像用血清肌氨酸酐的濃度或肌氨酸酐清除率來評估腎功能不全的程度一樣。但是單用此分類法或任何一種分類法仍嫌不足，為了可以更有效地預測肝功能不全對藥品藥動學與藥效學性質之影響，所以建議在使用</span><span style="color: black; font-size: 11pt;">Child-Pugh</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">分類法的同時，併用其他可能適用於評估肝功能的方法，例如：我國研究者於</span><span style="color: black; font-size: 11pt;">1992</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">年所發表的半乳糖單點法（</span><span style="color: black; font-size: 11pt;">Galactose Single Point, GSP</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）已為</span><span style="color: black; font-size: 11pt;">FDA</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">基準中所推薦，且已在國人常見肝病驗證過的一種用來評估殘餘之肝功能（</span><span style="color: black; font-size: 11pt;">residual liver function</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）的極為簡便可行的方法（詳見附錄﹔肝功能的評估）。</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;">&nbsp;</p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">基於上述的數據，簡式臨床試驗設計如能包括肝功能正常的受試者與</span><span style="color: black; font-size: 11pt;">Child-Pugh</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">分類為中度肝功能不全的病患，一般而言已經足夠。在這種情形下，在中度肝功能不全的病患的發現將可應用於輕度肝功能不全的病患，而重度肝功能不全的病患則通常列為禁忌</span><span style="color: black; font-size: 11pt;">(</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">詳見</span><span style="color: black; font-size: 11pt;"> &ldquo;</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">標示</span><span style="color: black; font-size: 11pt;">&rdquo; </span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">部份</span><span style="color: black; font-size: 11pt;">)</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">。然而對於治療範圍狹窄的藥品則應考慮進行基本完整的試驗設計，並配合臨床試驗的結果來修訂標示。</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">&nbsp; </span></p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">本基準的主要目的是希望能決定是否一個藥品或其代謝物的藥動學及</span><span style="color: black; font-size: 11pt;">/</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">或藥效學被改變的程度，已達到需要調整該藥在肝功能不全病患的使用劑量。基於這個理由，控制組的受試者應是肝功能正常的病患而不一定需要年輕健康的自願者。而且，控制組的年齡、體重及性別應儘可能的與肝功能不全組類似。根據藥品的性質，其他可能顯著影響藥品藥動之因素</span><span style="color: black; font-size: 11pt;">(</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">例如</span><span style="color: black; font-size: 11pt;">: </span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">飲食、抽煙、酒精攝取量、併用藥品、種族</span><span style="color: black; font-size: 11pt;">)</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">也應該考慮進去。對於已知具有遺傳多形性</span><span style="color: black; font-size: 11pt;">(genetic polymorphism</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">，例如</span><span style="color: black; font-size: 11pt;">: CYP2D6</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">或</span><span style="color: black; font-size: 11pt;">CYP2C19</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">酵素參與代謝的藥品</span><span style="color: black; font-size: 11pt;">)</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">，試驗委託者於分析結果時應考慮到受試者本身的代謝狀態。除了在參與臨床試驗前所作的標準檢驗項目外，試驗委託者可考慮利用標誌物如半乳糖、</span><span style="color: black; font-size: 11pt;">ICG</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">、</span><span style="color: black; font-size: 11pt;">antipyrine</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">或</span><span style="color: black; font-size: 11pt;">MEGX</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">來評估肝血流</span><span style="color: black; font-size: 11pt;">(hepatic blood flow)</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">或內在清除率</span><span style="color: black; font-size: 11pt;">(intrinsic clearance)</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">（詳見附錄：肝功能的評估）。此外，應該招募足夠數目的受試者，俾能收集到每組至少</span><span style="color: black; font-size: 11pt;">8</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">位可評估受試者的數據。</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;">&nbsp;</p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">（二）、藥品的給予</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">一個研究肝功能不全對藥品處置</span><span style="color: black; font-size: 11pt;">(drug disposition)</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">影響的臨床試驗，可設計為評估在給予單一或多次劑量藥品後，該藥品及其活性代謝物的藥動學性質。對於給予多次劑量試驗，應於給藥的第一天以及達到穩定狀態</span><span style="color: black; font-size: 11pt;">(steady state)</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">時評估其藥動學性質。如果曾有數據顯示由給予單一劑量的藥動學性質，可正確的推算出給予多次劑量時藥品及其活性代謝物的藥動性質，則只須執行單一劑量的臨床試驗。若於受試者所使用的藥品劑量範圍內，該藥品及其活性代謝物呈線性且不受時間影響的藥動學性質時則屬此類。當藥品或其活性代謝物呈非線性或會受時間影響的藥動學性質時，則給予多次劑量的臨床試驗則是必須的。雖然，臨床試驗計畫中所使用的臨床劑量通常是標示上所敘述的劑量，如對試驗受試者因肝功能不全而藥品血中濃度增加所致的毒性有所顧慮時，則可降低給予劑量。</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;">&nbsp;</p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">（三）、樣品採集與分析</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">血液樣品的採樣期程應足以決定藥品及其活性代謝物之末相半衰期</span><span style="color: black; font-size: 11pt;"> (terminal half-life)</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">，而且這個期程設計應可同時適用於控制組以及病患。對於被肝臟高度抽取的藥品</span><span style="color: black; font-size: 11pt;">( extraction ratio &gt; 0.7)</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">以及與血漿蛋白質高度結合的藥品</span><span style="color: black; font-size: 11pt;"> (fraction unbound &lt; 20%)</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">，至少在該藥血漿濃度最低</span><span style="color: black; font-size: 11pt;">(trough)</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">與最高</span><span style="color: black; font-size: 11pt;">(maximal)</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">時，測量其未結合狀態的比例。清除率及體積參數</span><span style="color: black; font-size: 11pt;">(volume parameters)</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">應以藥品於血漿及</span><span style="color: black; font-size: 11pt;">/</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">或血清中濃度</span><span style="color: black; font-size: 11pt;">(total concentration)</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">及未結合狀態濃度來表示。分析方法應有足夠的靈敏度與特異性俾能檢測出藥品及其活性代謝物。對於具有立體化學特性的藥品，藥品代謝的立體化學選擇性以及鏡像異構物</span><span style="color: black; font-size: 11pt;">(enantiomers)</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">與蛋白質結合的情形也應列入考慮。</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;">&nbsp;</p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><b><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">二、基本完整的臨床試驗設計</span></b><b><span style="color: black; font-size: 11pt;"> (Basic Full Study Design) </span></b></p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;">&nbsp;</p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">為了在標示中註明對各種肝功能不全病患的建議劑量，基本完整的臨床試驗設計應包括控制組以及依據</span><span style="color: black; font-size: 11pt;">Child-Pugh</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">分類法分類為輕度、中度與重度的病患，對於治療範圍狹窄之藥品宜配合附錄中的方法來定量肝功能，並依結果修正劑量與標示。此試驗應該招募足夠數目的受試者，俾能每組中至少有</span><span style="color: black; font-size: 11pt;">6</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">位可評估受試者的數據以供評估。此外，於本基準第四章第一節中考量的種種因素，也應在此臨床試驗設計列入考慮。</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;">&nbsp;</p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><b><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">三、群體藥動處理方式</span></b><b><span style="color: black; font-size: 11pt;">(Population PK Approach)</span></b></p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><b></b></p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">如果在第二階段或第三階段臨床試驗中未排除肝功能不全的病患，而且有足夠的藥動學資料來描述這些病患肝功能不全的特性，則從第二階段或第三階段臨床試驗中群體藥動學的篩選，可能有助於評估不同肝功能的變數</span><span style="color: black; font-size: 11pt;">(covariates)</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">對藥動學的影響。如果決定使用群體藥動學處理方式，則必須評估第二階段或第三階段臨床試驗中病患的腦病變</span><span style="color: black; font-size: 11pt;">(encephalopathy)</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">、腹水</span><span style="color: black; font-size: 11pt;">(ascites)</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">、血清膽紅素</span><span style="color: black; font-size: 11pt;"> (serum bilirubin)</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">、血清白蛋白</span><span style="color: black; font-size: 11pt;">(serum albumin)</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">、前凝血酵素時間</span><span style="color: black; font-size: 11pt;">(prothrombin time) (</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">以上是</span><span style="color: black; font-size: 11pt;">Child-Pugh</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">分類法的檢測項目</span><span style="color: black; font-size: 11pt;">)</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">、或是其他類似組合的肝功能檢測。</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;">&nbsp;</p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">一個群體藥動學研究應該包括</span><span style="color: black; font-size: 11pt;">:</span></p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">（一）預先計畫好的分析方法</span><span style="color: black; font-size: 11pt;">(pre-planned analysis)</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">來分析肝功能不全的影響。</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">（二）對於肝病嚴重程度的評估。</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">（三）足夠數目的病患以及足以代表各種不同肝功能不全的病患，以偵測到須要調整劑量的藥動變化。</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">（四）必要時，檢測未結合狀態的藥品濃度。</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">（五）檢測藥品及其活性代謝物。</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;">&nbsp;</p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">如果試驗委託者打算利用上述測試的結果來支持標示中註明肝功能不全病患不須調整劑量，以上的臨床試驗計畫特性將會非常重要。</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;">&nbsp;</p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><b><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">四、藥效學評估</span></b><b><span style="color: black; font-size: 11pt;"> (Pharmcodynamic Assessments)</span></b></p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">對於一個研究計畫是在評估肝功能改變所造成的影響時，尤其是在沒有濃度反應相關性的數據</span><span style="color: black; font-size: 11pt;"> (concentration-response data)</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">或是擔心肝功能改變也可能造成藥效反應的改變時，藥效學評估試驗是可能非常有用的。藥效學評估指標</span><span style="color: black; font-size: 11pt;"> (pharmacodynamic endpoints) </span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">的選擇應取決於藥品及其活性代謝物的藥理特性。</span> </p><span style="font-family: times new roman,serif; color: black; font-size: 11pt;"><br style="page-break-before: always;" clear="all" /></span><p style="text-align: center; line-height: 20pt;"><b><span style="font-family: 新細明體,serif; color: black;">第五章、數據分析</span> </b></p><p style="text-align: center; line-height: 20pt;"><b></b></p><p style="line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">數據分析的主要目的在於評估肝功能不全對於藥品及其活性代謝物藥動學性質的影響。如果可能的話，建立某一特定或某群肝功能評估方法（如</span><span style="color: black; font-size: 11pt;">Child-Pugh</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">或附錄中其他肝功能之定量測定方法）和相關藥動學測量及</span><span style="color: black; font-size: 11pt;">/</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">或參數的相關性，進而從這些資料建立肝功能不全病患的建議劑量。</span> </p><p style="line-height: 20pt;">&nbsp;</p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><b><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">一、參數預測</span></b><b> </b></p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">分析血中或尿中藥品濃度以預測藥品及其活性代謝物的藥動學參數，這些參數包括曲線下面積（</span><span style="color: black; font-size: 11pt;">AUC</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">），最高濃度（</span><span style="color: black; font-size: 11pt;">C<sub>max</sub></span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">），擬似清除率（</span><span style="color: black; font-size: 11pt;">apparent clearance CL/F</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">），腎及非腎清除率（</span><span style="color: black; font-size: 11pt;">CL<sub>R</sub></span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">及</span><span style="color: black; font-size: 11pt;">CL<sub>NR</sub></span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">），擬似分佈體積（</span><span style="color: black; font-size: 11pt;">V<sub>dz</sub> or V<sub>dss</sub></span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）及半衰期（</span><span style="color: black; font-size: 11pt;">t<sub>1/2</sub></span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）。必要時，這些參數可以藥品的非結合態表示（如</span> <span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">：</span><span style="color: black; font-size: 11pt;">CL<sub>u</sub>/F=Dose/AUC<sub>u</sub></span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">；</span><span style="color: black; font-size: 11pt;">u</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">代表未結合態藥品）。非室性模式</span><span style="color: black; font-size: 11pt;">(Noncompartment) </span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">或室性模式</span><span style="color: black; font-size: 11pt;">(compartment) </span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">的方式都可用來評估這些參數。</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;">&nbsp;</p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><b><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">二、肝功能測量與藥動學之相關性</span></b><b> </b></p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">過去經驗顯示，臨床上各種肝功能的測量，並無法像腎功能測量般成功的預測藥品藥動學性質的改變<b>。</b>用線性及非線性的模式可將肝功能異常與特定的藥動學參數建立相關性，肝功能異常的測量例如測量肝血流量、血清白蛋白濃度、前凝血酵素時間</span><span style="color: black; font-size: 11pt;">(prothrombin time)</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">、</span><span style="color: black; font-size: 11pt;">Child-Pugh</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">分類法及其它定量方法（如半乳糖單點法）等來判定，藥動學參數則包括總體清除率、口服清除率、擬似分佈體積、未結合態藥品的清除率或劑量標準化後的未結合態藥品曲線下面積等。使用迴歸方法分析肝功能不全及藥動學參數等連續性變數是適當的，但要了解有些相關性仍有賴於類別變數（如</span><span style="color: black; font-size: 11pt;">Child-Pugh</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">或附錄中其他肝功能之定量測定方法）。如果採模式化分析，結果應包含所選擇模式參數的預測值及測量精確度（如標準誤差或信賴區間）。誤差值的估計亦有助於模式適合性的評估。</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;">&nbsp;</p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><b><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">三、建議劑量的建立</span></b><b> </b></p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">肝功能不全病患臨床試驗的主要目的在於提供有關病患併有肝病時，藥品之起始劑量、給與間隔是否應做改變的建議，並且了解對此群體仍須小心調整劑量。依據臨床試驗的結果，試驗受試者或可於標示中宣稱肝功能不全並不會影響藥品的藥動學性質。基於這些臨床試驗的本質是屬於比較性質的，因此評估這類結果，以信賴區間（</span><span style="color: black; font-size: 11pt;">Confident interval </span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">表示方法將優於以顯著檢定方法（</span><span style="color: black; font-size: 11pt;">Significance test</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）表示。</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">建議劑量的建立一般可基於下列考量：</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">（一）如果肝功能不全對藥動學有明顯影響（例如增加</span><span style="color: black; font-size: 11pt;">2</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">倍以上），必要的劑量調整應註明於標示中。</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">（二）如果試驗受試者欲宣稱肝功能不全並不會影響藥品的藥動學性質，則必須具備下列條件之一：（</span><span style="color: black; font-size: 11pt;">1</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）根據試驗用藥已有的資料（如劑量及／或濃度與療效反應試驗），在試驗前描述</span><span style="color: black; font-size: 11pt;">&rdquo;</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">無影響界限</span><span style="color: black; font-size: 11pt;">&rdquo;</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">（</span><span style="color: black; font-size: 11pt;">no effect boundaries</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）；（</span><span style="color: black; font-size: 11pt;">2</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）在缺乏其他足以認定不同相等區間（</span><span style="color: black; font-size: 11pt;">equivalence interval</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）之資訊時，可以標準的</span><span style="color: black; font-size: 11pt;">90%</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">信賴區間</span><span style="color: black; font-size: 11pt;">(</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">即</span><span style="color: black; font-size: 11pt;">AUC</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">須落於</span><span style="color: black; font-size: 11pt;">80-125%</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">的範圍內，而且</span><span style="color: black; font-size: 11pt;">Cmax</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">須落於</span><span style="color: black; font-size: 11pt;">70-143%</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">的範圍內</span><span style="color: black; font-size: 11pt;">)</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">來適用於試驗用藥。因肝功能不全病患臨床試驗通常受試者人數較少，因此並不易確定於某一信賴區間範圍內，藥動學參數仍維持在某一</span><span style="color: black; font-size: 11pt;">&rdquo;</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">無影響界限</span><span style="color: black; font-size: 11pt;">&rdquo;</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">內。</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">（三）因為主要問題為處方用法、用量，群體相等性之標準（非個體相等性標準）對適用於控制組中藥動學測量或參數的變異性，可能有所幫助。此標準並不須重覆試驗設計。</span> </p><span style="font-family: times new roman,serif; color: black; font-size: 11pt;"><br style="page-break-before: always;" clear="all" /></span><p style="text-align: center; line-height: 20pt;"><b><span style="font-family: 新細明體,serif; color: black;">第六章、標示</span> </b></p><p style="text-align: center; line-height: 20pt;"><b></b></p><p style="line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">藥品標示應反應肝功能不全對藥品藥動學與藥效學的影響。雖然藥品的性質及肝功能不全對藥品的影響使得標示不易，但對使用</span><span style="color: black; font-size: 11pt;">Child-Pugh</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">分類法，並配合附錄中其他定量測定方法評估肝功能之後，列為中度肝功能不全病患，如試驗用藥品之清除率有顯著降低時，應減低其藥品劑量。一般而言，依</span><span style="color: black; font-size: 11pt;">Child-Pugh</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">分類法歸類為輕度肝功能不全的病患也應作類似的劑量調整。依據藥品的使用及治療指標</span><span style="color: black; font-size: 11pt;">(therapeutic index)</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">的寬窄，對</span><span style="color: black; font-size: 11pt;">Child-Pugh</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">分類法歸類為重度肝功能不全病患，可能要列為「禁忌」或特別小心使用。</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;">&nbsp;</p><p style="line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">反之，如果臨床試驗結果顯示中度肝功能不全病患的藥品排除率並無顯著改變，則藥品可用於輕度及中度肝功能不全病患而無需調整其劑量。依據藥品的使用與治療指標的寬窄，通常對重度肝功能不全病患應標示小心使用。</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">　　</span> </p><p style="line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">如果依據第三章第二節中所列的理由而不須執行肝功能不全病患之臨床試驗，則標示中應標明肝功能不全對藥品的影響未曾測試且可能不須要調整劑量。</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;">&nbsp;</p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><b><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">一、臨床藥理學</span></b><b> </b></p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">（一）藥動學</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">藥動學應包括藥品的：</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: wingdings; color: black; font-size: 11pt;">l<span style="font: 7pt times new roman;">&nbsp;&nbsp; </span></span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">肝臟排除的機轉（酵素途徑，尿甘酸化結合度</span><span style="color: black; font-size: 11pt;">(glucuronidation)</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">及膽汁排除等）。</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: wingdings; color: black; font-size: 11pt;">l<span style="font: 7pt times new roman;">&nbsp;&nbsp; </span></span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">藥品被肝臟排除的比例。</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: wingdings; color: black; font-size: 11pt;">l<span style="font: 7pt times new roman;">&nbsp;&nbsp; </span></span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">代謝物在肝功能不全病患之藥動學（如果適用）。</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt; margin: 0cm -7.7pt 0pt 72pt;"><span style="font-family: wingdings; color: black; font-size: 11pt;">l<span style="font: 7pt times new roman;">&nbsp;&nbsp; </span></span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">肝功能不全對藥品及其代謝物之蛋白質結合度的影響（如果適用）。</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: wingdings; color: black; font-size: 11pt;">l<span style="font: 7pt times new roman;">&nbsp;&nbsp; </span></span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">肝功能不全對消旋異構物中鏡像異構物的立體選擇處置（如果有證據顯示不同立體異構物中有不同活性或毒性）。</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">&nbsp;&nbsp;&nbsp; </span></p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">（二）特殊群體（</span><span style="color: black; font-size: 11pt;">Special Populations</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">應簡短的重述藥動學之變化及說明肝功能不全病患藥效性質之改變及劑量之調整。這些訊息應基於依本基準所建議各項試驗或可接受之替代試驗所得的結果。必要之資訊亦應標示於警語（</span><span style="color: black; font-size: 11pt;">WARNINGS</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）、注意事項（</span><span style="color: black; font-size: 11pt;">PRECAUTIONS</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）、禁忌（</span><span style="color: black; font-size: 11pt;">CONTRAINDICATIONS</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）及用法用量（</span><span style="color: black; font-size: 11pt;">DOSAGE AND ADMINISTRATION</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）等。</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;">&nbsp;</p><p style="line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">例一：</span><span style="font-family: times new roman,serif; color: black; font-size: 11pt;">&nbsp;&nbsp;&nbsp; </span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">最簡單的情形是在肝功能不全病患執行臨床試驗，結果顯示藥品的藥動學及藥效學甚少或並未改變，標示內容建議如下：</span> </p><p style="line-height: 20pt;">&nbsp;</p><table style="margin: auto auto auto 55.4pt; border-collapse: collapse;border: medium none;" border="1" cellspacing="0" cellpadding="0"> <tbody> <tr> <td style="padding-bottom: 0cm; background-color: transparent; padding-left: 1.4pt; width: 362.7pt; padding-right: 1.4pt; padding-top: 0cm;border: windowtext 1pt solid;" valign="top"> <p style="line-height: 20pt;"><i><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">在一項比較</span></i><i><span style="font-family: times new roman,serif; color: black; font-size: 11pt;">8</span></i><i><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">個中度肝功能不全病患（依</span></i><i><span style="font-family: times new roman,serif; color: black; font-size: 11pt;">Child-Pugh</span></i><i><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">分類法評估，並配合附錄中其他肝功能之定量測定方法所得數據評估肝功能）與</span></i><i><span style="font-family: times new roman,serif; color: black; font-size: 11pt;">8</span></i><i><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">個正常肝功能受試者的臨床試驗中，給予單一劑量及</span></i><i><span style="font-family: times new roman,serif; color: black; font-size: 11pt;">/</span></i><i><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">或多次劑量，（ˍ藥品名稱）於肝功能不全病患，並未發現藥動／藥效學性質改變，因此於輕度及中度肝功能不全病患並不需調整用法用量。</span></i> </p> </td> </tr> </tbody></table><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;">&nbsp;</p><p style="line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">例二：</span><span style="color: black; font-size: 11pt;">&nbsp;&nbsp;&nbsp; </span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">當肝功能不全會影響藥品的藥動學及藥效學性質時，依據已知的藥品性質（例如消旋異構物中具不同活性的立體異構物，包括活性或毒性的代謝物）以及依據本基準所執行的臨床試驗所得到的結果，可適度修改標示如下：</span> </p><p style="line-height: 20pt;">&nbsp;</p><table style="margin: auto auto auto 55.4pt; border-collapse: collapse;border: medium none;" border="1" cellspacing="0" cellpadding="0"> <tbody> <tr> <td style="padding-bottom: 0cm; background-color: transparent; padding-left: 1.4pt; width: 362.7pt; padding-right: 1.4pt; padding-top: 0cm;border: windowtext 1pt solid;" valign="top"> <p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><i><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">比較（ˍ藥品名稱）在肝功能不全病患及正常肝功能受試者的藥動性質，（ˍ藥品名稱）</span></i><i><span style="color: black; font-size: 11pt;">/</span></i><i><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">代謝物的全體清除率在中度肝功能不全病患（經</span></i><i><span style="color: black; font-size: 11pt;">Child-Pugh</span></i><i><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">分類法評估）降低了ˍ（％）；在中度肝功能不全病患，（ˍ藥品名稱）</span></i><i><span style="color: black; font-size: 11pt;">/</span></i><i><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">代謝物的半衰期延長了</span></i><i><span style="color: black; font-size: 11pt;">__(</span></i><i><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">時間</span></i><i><span style="color: black; font-size: 11pt;">)</span></i><i><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">。（ˍ藥品名稱）</span></i><i><span style="color: black; font-size: 11pt;">/</span></i><i><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">代謝物的蛋白質結合率在肝功能不全病患上有（或無）改變。在長期給藥後，（ˍ藥品名稱）</span></i><i><span style="color: black; font-size: 11pt;">/</span></i><i><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">代謝物在肝功能不全病患會蓄積到</span></i><i><span style="color: black; font-size: 11pt;">___</span></i><i><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">之程度。在輕度及中度肝功能不全病患，（ˍ藥品名稱）的劑量應降低。在重度肝功能不全病患，（ˍ藥品名稱）的使用應特別注意或禁止使用</span></i><i><span style="color: black; font-size: 11pt;">(</span></i><i><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">請參照用法用量</span></i><i><span style="color: black; font-size: 11pt;">)</span></i><i><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">。</span></i> </p> </td> </tr> </tbody></table><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;">&nbsp;</p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">例三：</span><span style="color: black; font-size: 11pt;">&nbsp;&nbsp;&nbsp; </span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">當無肝功能不全病患的資料來作為標示的依據時，標示的內容如下：</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">1.</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">藥品不經過肝臟排除</span><span style="color: black; font-size: 11pt;">(elimination)</span></p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;">&nbsp;</p><table style="margin: auto auto auto 55.4pt; border-collapse: collapse;border: medium none;" border="1" cellspacing="0" cellpadding="0"> <tbody> <tr> <td style="padding-bottom: 0cm; background-color: transparent; padding-left: 1.4pt; width: 362.7pt; padding-right: 1.4pt; padding-top: 0cm;border: windowtext 1pt solid;" valign="top"> <p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><i><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">肝功能不全對（ˍ藥品名稱）藥動性質的影響未經評估。因為大於</span></i><i><span style="color: black; font-size: 11pt;">90%</span></i><i><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">的給藥劑量以原型經由尿液排出，肝功能不全應不至顯著影響（ˍ藥品名稱）之排除。</span></i> </p> </td> </tr> </tbody></table><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><i></i></p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">2.</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">少部份經由肝臟排除（</span><span style="color: black; font-size: 11pt;">Hepatic elimination &lt;20</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">﹪）</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">(1)</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">治療指標較廣的藥品</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;">&nbsp;</p><table style="margin: auto auto auto 55.4pt; border-collapse: collapse;border: medium none;" border="1" cellspacing="0" cellpadding="0"> <tbody> <tr> <td style="padding-bottom: 0cm; background-color: transparent; padding-left: 1.4pt; width: 362.7pt; padding-right: 1.4pt; padding-top: 0cm;border: windowtext 1pt solid;" valign="top"> <p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><i><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">肝功能不全對（ˍ藥品名稱）藥動性質的影響未經評估。因為大於</span></i><i><span style="color: black; font-size: 11pt;">80%</span></i><i><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">的給藥劑量以原型經由尿液排出，肝功能不全應不至顯著影響（ˍ藥品名稱）血中濃度而影響其安全性。如果病患也有腎衰竭的情形，肝臟排除藥品的重要性會增加。相較於肝功能正常之受試者，可能需要降低肝功能不全病患之起始及維持劑量或者延長給藥間隔</span></i><i><span style="color: black; font-size: 11pt;">(</span></i><i><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">請參照注意事項</span></i><i><span style="color: black; font-size: 11pt;">)</span></i><i><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">。</span></i> </p> </td> </tr> </tbody></table><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><i></i></p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">(2)</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">治療指標狹窄的藥品</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;">&nbsp;</p><table style="margin: auto auto auto 55.4pt; border-collapse: collapse;border: medium none;" border="1" cellspacing="0" cellpadding="0"> <tbody> <tr> <td style="padding-bottom: 0cm; background-color: transparent; padding-left: 1.4pt; width: 362.7pt; padding-right: 1.4pt; padding-top: 0cm;border: windowtext 1pt solid;" valign="top"> <p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><i><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">肝功能不全對（ˍ藥品名稱）的藥動學性質影響未經評估，因為此藥的一般治療劑量與引起藥品不良反應之劑量相近。而且從體內（</span></i><i><span style="color: black; font-size: 11pt;">in vivo</span></i><i><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）或體外（</span></i><i><span style="color: black; font-size: 11pt;">in vitro</span></i><i><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）的證據中顯示，（ˍ藥品名稱）會經由肝臟排除，因此肝功能不全可能會增加藥品不良反應的發生機率。相較於肝功能正常之受試者，可能需要降低（ˍ藥品名稱）在肝功能不全病患的起始及維持劑量或是延長其給藥間隔。如果病患有腎衰竭的現象，肝臟排除藥品的重要性會因而增加，所以此類病患應避免使用（ˍ藥品名稱），如須使用（ˍ藥品名稱）必須特別小心監視。</span></i> </p> </td> </tr> </tbody></table><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">　　</span><i> </i></p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">3.</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">主要經由肝臟排除</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">(1)</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">治療指標較廣之藥品</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;">&nbsp;</p><table style="margin: auto auto auto 55.4pt; border-collapse: collapse;border: medium none;" border="1" cellspacing="0" cellpadding="0"> <tbody> <tr> <td style="padding-bottom: 0cm; background-color: transparent; padding-left: 1.4pt; width: 362.7pt; padding-right: 1.4pt; padding-top: 0cm;border: windowtext 1pt solid;" valign="top"> <p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><i><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">肝功能不全對於（ˍ藥品名稱）藥動學性質的影響未經評估。因為有體內及體外的證據顯示（ˍ藥品名稱）主要經由肝臟代謝，因此預期肝功能不全可能會顯著改變（ˍ藥品名稱）的藥動學性質。</span></i><i> </i></p> <p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><i><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">相較於肝功能正常之受試者，在肝功能不全病患使用此藥應特別小心，而且可能必須降低起始及維持劑量或是延長其給藥間隔。</span></i> </p> </td> </tr> </tbody></table><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">　　　　</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">(2)</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">治療指標狹窄之藥品</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;">&nbsp;</p><table style="margin: auto auto auto 55.4pt; border-collapse: collapse;border: medium none;" border="1" cellspacing="0" cellpadding="0"> <tbody> <tr> <td style="padding-bottom: 0cm; background-color: transparent; padding-left: 1.4pt; width: 362.7pt; padding-right: 1.4pt; padding-top: 0cm;border: windowtext 1pt solid;" valign="top"> <p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><i><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">肝功能不全對於（ˍ藥品名稱）的藥動學性質的影響未經評估。因為小於</span></i><i><span style="color: black; font-size: 11pt;">20%</span></i><i><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">的給藥劑量會以原型經由尿液排出，而且有體外及體內的證據顯示該藥品主要經由肝臟代謝。肝功能不全可能會顯著影響（ˍ藥品名稱）的藥動學性質。（ˍ藥品名稱）應不能使用於肝功能不全病患，如必須要用，應特別小心。</span></i><i><span style="color: black; font-size: 11pt;">(</span></i><i><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">請參照禁忌</span></i><i><span style="color: black; font-size: 11pt;">)</span></i> </p> </td> </tr> </tbody></table><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><i></i></p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">4.</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">肝臟排除尚不明確</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">在這種情形下，此藥品視為會顯著經由肝臟代謝而適用上述標示。</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;">&nbsp;</p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><b><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">二、注意事項及警語</span></b><b> </b></p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">如果肝功能不全病患會引起藥動學及藥效學臨床上的重要改變，則這些訊息應包括在「注意事項」並參考「用法用量」。如果已知藥品有狹窄的治療指標，則應在「警語」或「禁忌」中註明。</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;">&nbsp;</p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><b><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">三、用法用量</span></b><b> </b></p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">應於適當處註明下列文字，例如：</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;">&nbsp;</p><table style="margin: auto auto auto 55.4pt; border-collapse: collapse;border: medium none;" border="1" cellspacing="0" cellpadding="0"> <tbody> <tr> <td style="padding-bottom: 0cm; background-color: transparent; padding-left: 1.4pt; width: 362.7pt; padding-right: 1.4pt; padding-top: 0cm;border: windowtext 1pt solid;" valign="top"> <p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><i><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">肝功能不全對（ˍ藥品名稱）的藥動學或藥效學性質的影響並不顯著，因此不須調整劑量。</span></i> </p> </td> </tr> </tbody></table><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;">&nbsp;</p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">惟因肝功能不全而須調整劑量時，仍應列入適當的資訊。</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;">&nbsp;</p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">此外，複方製劑也須特別考量。如果有足夠的證據顯示肝功能不全病患對於複方中個別成分的藥動學性質有類似的影響，則應依肝功能不全之程度適度調整劑量。否則，應依以下的文字標示：</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;">&nbsp;</p><table style="margin: auto auto auto 55.4pt; border-collapse: collapse;border: medium none;" border="1" cellspacing="0" cellpadding="0"> <tbody> <tr> <td style="padding-bottom: 0cm; background-color: transparent; padding-left: 1.4pt; width: 362.7pt; padding-right: 1.4pt; padding-top: 0cm;border: windowtext 1pt solid;" valign="top"> <p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><i><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">因為在固定比例的複方製劑中，各別成份無法訂定，肝功能不全會降低藥品清除率，而對複方中</span></i><i><span style="color: black; font-size: 11pt;">A</span></i><i><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">成分的影響遠大於對複方中</span></i><i><span style="color: black; font-size: 11pt;">B </span></i><i><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">成分的影響，所以肝功能不全病患應避免使用此複方（必要時，詳見「注意事項」與「警語」）。</span></i> </p> </td> </tr> </tbody></table><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;">&nbsp;</p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">如果複方中各成份的比例不同，且有各成份比例不同的複方製劑可供選擇，則儘可能要求醫師使用較少經由肝臟代謝成份的產品。</span> </p></div><span style="font-family: times new roman,serif; color: black; font-size: 11pt;"><br style="page-break-before: always;" clear="all" /></span><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">參考文獻</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;">&nbsp;</p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 24pt;"><span style="color: black; font-size: 11pt;">1.</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">行政院衛生署</span><span style="color: black; font-size: 11pt;">(1997). </span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">藥品臨床試驗申請須知（台北）</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 24pt;"><span style="color: black; font-size: 11pt;">2.</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">行政院衛生署</span><span style="color: black; font-size: 11pt;">(1999). </span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">藥品查驗登記審查準則（台北）</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 24pt;"><span style="color: black; font-size: 11pt;">3.</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">行政院衛生署</span><span style="color: black; font-size: 11pt;">(2000). </span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">藥品非臨床試驗安全性規範（台北）</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 24pt;"><span style="color: black; font-size: 11pt;">4.</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">行政院衛生署</span><span style="color: black; font-size: 11pt;">(2000). </span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">臨床試驗基準（台北）</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 24pt;"><span style="color: black; font-size: 11pt;">5.</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">行政院衛生署</span><span style="color: black; font-size: 11pt;">(2000). </span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">藥品非臨床試驗優良操作規範（台北）</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 24pt;"><span style="color: black; font-size: 11pt;">6.Draft Guidance for Inducstry, Pharmacokinetics in Patients with Impaired Hepatic Function:Study Design, Data Analysis, and Impact on Dosing and Labeling. FDA, USA, 1999.</span></p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 24pt;"><span style="color: black; font-size: 11pt;">7.Hu O.Y-P., Tang, H.S., and C.L. Chang, 1994, "The Influence of Chronic Lobular Hepatitis on Pharmacokinetics of Cefoperazone</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">－</span><span style="color: black; font-size: 11pt;">A Novel Galactose Single-point Method as a Measure of Residual Liver Function." <i>Biopharm. Drug Dispos, 15(7): 563-576</i>.</span></p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 24pt;"><span style="color: black; font-size: 11pt;">8.Hu O.Y-P., Tang, H.S., and C.L. Chang, 1995, "Novel Galactose Single-point Method as a Measure of Residual Liver Function:Example of Cefoperazone Kinetics in Patients with Liver Cirrhosis." <i>J. Clin. Pharmacol. 35(3): 250-258</i>.</span></p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 24pt;"><span style="color: black; font-size: 11pt;">9.Shargel L. and A. Yu. 1999. <i>Applied Biopharmaceutics &amp; Pharmacokinetics. 4<sup>th</sup> ed., p.566,</i> Prentice-Hall International, Inc.</span></p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 24pt;"><span style="color: black; font-size: 11pt;">10.Tang, H. -S., O.Y.-P. Hu., 1992, "Assessment of Liver Function Using a Novel Galactose Single Point Method," <i>Digestion, 52:222-231</i>.</span></p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;">&nbsp;</p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;">&nbsp;</p><span style="font-family: times new roman,serif; color: black; font-size: 11pt;"><br style="page-break-before: always;" clear="all" /></span><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;">&nbsp;</p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">附錄：肝功能的評估</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;">&nbsp;</p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">1</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">、</span><span style="color: black; font-size: 11pt;">Child-Pugh</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">系統</span> </p><table style="border-collapse: collapse;border: medium none;" border="1" cellspacing="0" cellpadding="0"> <tbody> <tr style="page-break-inside: avoid;"> <td style="padding-bottom: 0cm; background-color: transparent; padding-left: 1.4pt; width: 136.4pt; padding-right: 1.4pt; padding-top: 0cm;border: windowtext 1pt solid;" valign="top" rowspan="2"> <p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;">&nbsp;</p> </td> <td style="border-bottom: windowtext 1pt solid; padding-bottom: 0cm; background-color: transparent; padding-left: 1.4pt; width: 281.7pt; padding-right: 1.4pt; border-left-color: #f0f0f0; border-top: windowtext 1pt solid; border-right: windowtext 1pt solid; padding-top: 0cm;" valign="top" colspan="3"> <p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">觀察結果所得點數</span> </p> </td> </tr> <tr style="page-break-inside: avoid;"> <td style="border-bottom: windowtext 1pt solid; padding-bottom: 0cm; background-color: transparent; border-top-color: #f0f0f0; padding-left: 1.4pt; width: 72.6pt; padding-right: 1.4pt; border-left-color: #f0f0f0; border-right: windowtext 1pt solid; padding-top: 0cm;" valign="top"> <p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">1</span></p> </td> <td style="border-bottom: windowtext 1pt solid; padding-bottom: 0cm; background-color: transparent; border-top-color: #f0f0f0; padding-left: 1.4pt; width: 104.55pt; padding-right: 1.4pt; border-left-color: #f0f0f0; border-right: windowtext 1pt solid; padding-top: 0cm;" valign="top"> <p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">2</span></p> </td> <td style="border-bottom: windowtext 1pt solid; padding-bottom: 0cm; background-color: transparent; border-top-color: #f0f0f0; padding-left: 1.4pt; width: 104.55pt; padding-right: 1.4pt; border-left-color: #f0f0f0; border-right: windowtext 1pt solid; padding-top: 0cm;" valign="top"> <p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">3</span></p> </td> </tr> <tr> <td style="border-bottom: windowtext 1pt solid; border-left: windowtext 1pt solid; padding-bottom: 0cm; background-color: transparent; border-top-color: #f0f0f0; padding-left: 1.4pt; width: 136.4pt; padding-right: 1.4pt; border-right: windowtext 1pt solid; padding-top: 0cm;" valign="top"> <p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">腦病變程度</span><span style="color: black; font-size: 11pt;">*</span></p> </td> <td style="border-bottom: windowtext 1pt solid; padding-bottom: 0cm; background-color: transparent; border-top-color: #f0f0f0; padding-left: 1.4pt; width: 72.6pt; padding-right: 1.4pt; border-left-color: #f0f0f0; border-right: windowtext 1pt solid; padding-top: 0cm;" valign="top"> <p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">無</span> </p> </td> <td style="border-bottom: windowtext 1pt solid; padding-bottom: 0cm; background-color: transparent; border-top-color: #f0f0f0; padding-left: 1.4pt; width: 104.55pt; padding-right: 1.4pt; border-left-color: #f0f0f0; border-right: windowtext 1pt solid; padding-top: 0cm;" valign="top"> <p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">1</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">或</span><span style="color: black; font-size: 11pt;">2</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">級</span> </p> </td> <td style="border-bottom: windowtext 1pt solid; padding-bottom: 0cm; background-color: transparent; border-top-color: #f0f0f0; padding-left: 1.4pt; width: 104.55pt; padding-right: 1.4pt; border-left-color: #f0f0f0; border-right: windowtext 1pt solid; padding-top: 0cm;" valign="top"> <p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">3</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">或</span><span style="color: black; font-size: 11pt;">4</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">級</span> </p> </td> </tr> <tr> <td style="border-bottom: windowtext 1pt solid; border-left: windowtext 1pt solid; padding-bottom: 0cm; background-color: transparent; border-top-color: #f0f0f0; padding-left: 1.4pt; width: 136.4pt; padding-right: 1.4pt; border-right: windowtext 1pt solid; padding-top: 0cm;" valign="top"> <p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">腹水</span> </p> </td> <td style="border-bottom: windowtext 1pt solid; padding-bottom: 0cm; background-color: transparent; border-top-color: #f0f0f0; padding-left: 1.4pt; width: 72.6pt; padding-right: 1.4pt; border-left-color: #f0f0f0; border-right: windowtext 1pt solid; padding-top: 0cm;" valign="top"> <p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">無</span> </p> </td> <td style="border-bottom: windowtext 1pt solid; padding-bottom: 0cm; background-color: transparent; border-top-color: #f0f0f0; padding-left: 1.4pt; width: 104.55pt; padding-right: 1.4pt; border-left-color: #f0f0f0; border-right: windowtext 1pt solid; padding-top: 0cm;" valign="top"> <p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">輕度</span> </p> </td> <td style="border-bottom: windowtext 1pt solid; padding-bottom: 0cm; background-color: transparent; border-top-color: #f0f0f0; padding-left: 1.4pt; width: 104.55pt; padding-right: 1.4pt; border-left-color: #f0f0f0; border-right: windowtext 1pt solid; padding-top: 0cm;" valign="top"> <p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">中度</span> </p> </td> </tr> <tr> <td style="border-bottom: windowtext 1pt solid; border-left: windowtext 1pt solid; padding-bottom: 0cm; background-color: transparent; border-top-color: #f0f0f0; padding-left: 1.4pt; width: 136.4pt; padding-right: 1.4pt; border-right: windowtext 1pt solid; padding-top: 0cm;" valign="top"> <p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">血清膽紅素濃度（</span><span style="color: black; font-size: 11pt;">mg/dl</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）</span> </p> </td> <td style="border-bottom: windowtext 1pt solid; padding-bottom: 0cm; background-color: transparent; border-top-color: #f0f0f0; padding-left: 1.4pt; width: 72.6pt; padding-right: 1.4pt; border-left-color: #f0f0f0; border-right: windowtext 1pt solid; padding-top: 0cm;" valign="top"> <p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">＜</span><span style="color: black; font-size: 11pt;">2</span></p> </td> <td style="border-bottom: windowtext 1pt solid; padding-bottom: 0cm; background-color: transparent; border-top-color: #f0f0f0; padding-left: 1.4pt; width: 104.55pt; padding-right: 1.4pt; border-left-color: #f0f0f0; border-right: windowtext 1pt solid; padding-top: 0cm;" valign="top"> <p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">2</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">至</span><span style="color: black; font-size: 11pt;">3</span></p> </td> <td style="border-bottom: windowtext 1pt solid; padding-bottom: 0cm; background-color: transparent; border-top-color: #f0f0f0; padding-left: 1.4pt; width: 104.55pt; padding-right: 1.4pt; border-left-color: #f0f0f0; border-right: windowtext 1pt solid; padding-top: 0cm;" valign="top"> <p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">＞</span><span style="color: black; font-size: 11pt;">3</span></p> </td> </tr> <tr> <td style="border-bottom: windowtext 1pt solid; border-left: windowtext 1pt solid; padding-bottom: 0cm; background-color: transparent; border-top-color: #f0f0f0; padding-left: 1.4pt; width: 136.4pt; padding-right: 1.4pt; border-right: windowtext 1pt solid; padding-top: 0cm;" valign="top"> <p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">血清白蛋白濃度（</span><span style="color: black; font-size: 11pt;">g/dl</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）</span> </p> </td> <td style="border-bottom: windowtext 1pt solid; padding-bottom: 0cm; background-color: transparent; border-top-color: #f0f0f0; padding-left: 1.4pt; width: 72.6pt; padding-right: 1.4pt; border-left-color: #f0f0f0; border-right: windowtext 1pt solid; padding-top: 0cm;" valign="top"> <p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">＞</span><span style="color: black; font-size: 11pt;">3.5</span></p> </td> <td style="border-bottom: windowtext 1pt solid; padding-bottom: 0cm; background-color: transparent; border-top-color: #f0f0f0; padding-left: 1.4pt; width: 104.55pt; padding-right: 1.4pt; border-left-color: #f0f0f0; border-right: windowtext 1pt solid; padding-top: 0cm;" valign="top"> <p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">2.8</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">至</span><span style="color: black; font-size: 11pt;">3.5</span></p> </td> <td style="border-bottom: windowtext 1pt solid; padding-bottom: 0cm; background-color: transparent; border-top-color: #f0f0f0; padding-left: 1.4pt; width: 104.55pt; padding-right: 1.4pt; border-left-color: #f0f0f0; border-right: windowtext 1pt solid; padding-top: 0cm;" valign="top"> <p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">＜</span><span style="color: black; font-size: 11pt;">2.8</span></p> </td> </tr> <tr> <td style="border-bottom: windowtext 1pt solid; border-left: windowtext 1pt solid; padding-bottom: 0cm; background-color: transparent; border-top-color: #f0f0f0; padding-left: 1.4pt; width: 136.4pt; padding-right: 1.4pt; border-right: windowtext 1pt solid; padding-top: 0cm;" valign="top"> <p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">前凝血酵素時間延長秒數</span> </p> </td> <td style="border-bottom: windowtext 1pt solid; padding-bottom: 0cm; background-color: transparent; border-top-color: #f0f0f0; padding-left: 1.4pt; width: 72.6pt; padding-right: 1.4pt; border-left-color: #f0f0f0; border-right: windowtext 1pt solid; padding-top: 0cm;" valign="top"> <p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">＜</span><span style="color: black; font-size: 11pt;">4</span></p> </td> <td style="border-bottom: windowtext 1pt solid; padding-bottom: 0cm; background-color: transparent; border-top-color: #f0f0f0; padding-left: 1.4pt; width: 104.55pt; padding-right: 1.4pt; border-left-color: #f0f0f0; border-right: windowtext 1pt solid; padding-top: 0cm;" valign="top"> <p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">4</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">至</span><span style="color: black; font-size: 11pt;">6</span></p> </td> <td style="border-bottom: windowtext 1pt solid; padding-bottom: 0cm; background-color: transparent; border-top-color: #f0f0f0; padding-left: 1.4pt; width: 104.55pt; padding-right: 1.4pt; border-left-color: #f0f0f0; border-right: windowtext 1pt solid; padding-top: 0cm;" valign="top"> <p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">＞</span><span style="color: black; font-size: 11pt;">6</span></p> </td> </tr> </tbody></table><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">*0</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">級：意識、人格、神經學檢查、腦電圖均正常</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">&nbsp;1</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">級：不安，睡眠不良，易受刺激，躁動、四肢顫抖，無法寫字，腦波出現</span><span style="color: black; font-size: 11pt;">5Hz</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">慢波</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">&nbsp;2</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">級：嗜睡，時間認知差，情感表現不適，運動障礙，運動失調，腦波出現三相慢波</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">&nbsp;3</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">級：倦睡，木僵，對地方認知差，反射增強，僵直，腦波出現慢波</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">&nbsp;4</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">級：無法喚醒的昏迷，人格及行為喪失，去大腦姿勢，腦波出現</span><span style="color: black; font-size: 11pt;">2-3Hz</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">慢波</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">評估結果為</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">（</span><span style="color: black; font-size: 11pt;">1</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）</span><span style="color: black; font-size: 11pt;">5-6</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">分：表示低開刀風險，即肝功能受損較輕微；</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">（</span><span style="color: black; font-size: 11pt;">2</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）</span><span style="color: black; font-size: 11pt;">7-9</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">分：表示中度開刀風險，即肝功能受損為中度；</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">（</span><span style="color: black; font-size: 11pt;">3</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）</span><span style="color: black; font-size: 11pt;">10-15</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">分：表示高開刀風險，即肝功能受損較嚴重（此為酒精性肝硬化病人之外科手術評估）。</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;">&nbsp;</p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">2</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">、半乳糖單點法（</span><span style="color: black; font-size: 11pt;">Galactose Single Point, GSP</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）</span><b> </b></p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; font-size: 11pt;">本法乃是由唐鴻舜及胡幼圃發表於</span><span style="font-size: 11pt;">1992</span><span style="font-family: 新細明體,serif; font-size: 11pt;">年之</span><span style="font-size: 11pt;">Digestion</span><span style="font-family: 新細明體,serif; font-size: 11pt;">期刊中。</span><span style="font-size: 11pt;">GSP</span><span style="font-family: 新細明體,serif; font-size: 11pt;">為於空腹時，三分鐘快速靜脈輸注</span><span style="font-size: 11pt;">0.5 g/kg</span><span style="font-family: 新細明體,serif; font-size: 11pt;">的半乳糖，經過</span><span style="font-size: 11pt;">60</span><span style="font-family: 新細明體,serif; font-size: 11pt;">分鐘後，測量受試者血中半乳糖的濃度，即為其</span><span style="font-size: 11pt;">GSP</span><span style="font-family: 新細明體,serif; font-size: 11pt;">值（單位為</span><span style="font-family: symbol; font-size: 11pt;">m</span><span style="font-size: 11pt;">g/ml</span><span style="font-family: 新細明體,serif; font-size: 11pt;">）。血中半乳糖濃度，和肝功能異常有靈敏的相關性，且實驗數據顯示</span><span style="font-size: 11pt;">GSP</span><span style="font-family: 新細明體,serif; font-size: 11pt;">值與肝功能異常的程度有非常顯著的關係。因此，可經由受試者的</span><span style="font-size: 11pt;">GSP</span><span style="font-family: 新細明體,serif; font-size: 11pt;">值來評估其肝臟的剩餘功能，評估方法如下：</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-size: 11pt;">(1)<span style="font: 7pt times new roman;">&nbsp; </span></span><span style="font-size: 11pt;">GSP</span><span style="font-family: 新細明體,serif; font-size: 11pt;">值小於</span><span style="font-size: 11pt;">280</span><span style="font-family: symbol; font-size: 11pt;">m</span><span style="font-size: 11pt;">g/ml</span><span style="font-family: 新細明體,serif; font-size: 11pt;">：肝功能正常或受損輕微。</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-size: 11pt;">(2)<span style="font: 7pt times new roman;">&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; </span></span><span style="font-size: 11pt;">GSP</span><span style="font-family: 新細明體,serif; font-size: 11pt;">值介於</span><span style="font-size: 11pt;">280</span><span style="font-family: 新細明體,serif; font-size: 11pt;">與</span><span style="font-size: 11pt;">480</span><span style="font-family: symbol; font-size: 11pt;">m</span><span style="font-size: 11pt;">g/ml</span><span style="font-family: 新細明體,serif; font-size: 11pt;">之間：肝功能受損為中度（可能為慢性肝炎患者）。</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-size: 11pt;">(3)<span style="font: 7pt times new roman;">&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; </span></span><span style="font-size: 11pt;">GSP</span><span style="font-family: 新細明體,serif; font-size: 11pt;">值大於</span><span style="font-size: 11pt;">480</span><span style="font-family: symbol; font-size: 11pt;">m</span><span style="font-size: 11pt;">g/ml</span><span style="font-family: 新細明體,serif; font-size: 11pt;">：肝功能受損較嚴重（可能為肝硬化或肝癌患者）。</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;">&nbsp;</p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">3</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">、</span><span style="color: black; font-size: 11pt;">Maddrey</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">辨識功能</span><span style="color: black; font-size: 11pt;">( Maddrey Discriminant Function, df )</span></p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">&nbsp;&nbsp; df</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">＝</span><span style="color: black; font-size: 11pt;">4.6&times;</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">前凝血酵素時間（秒）＋血清總膽紅素（</span><span style="color: black; font-size: 11pt;">mg/dl</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">&nbsp;&nbsp; </span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">以</span><span style="color: black; font-size: 11pt;">df</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">值來評估急性酒精性肝炎病人之病情可分下列情形：</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">　</span> <span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">如果</span><span style="color: black; font-size: 11pt;">df</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">值小於</span><span style="color: black; font-size: 11pt;">54</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">，則該疾病並不嚴重</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">&nbsp;&nbsp; </span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">如果</span><span style="color: black; font-size: 11pt;">df</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">值介於</span><span style="color: black; font-size: 11pt;">55</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">到</span><span style="color: black; font-size: 11pt;">92</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">之間，則該疾病嚴重</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">&nbsp;&nbsp; </span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">如果</span><span style="color: black; font-size: 11pt;">df</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">值大於或等於</span><span style="color: black; font-size: 11pt;">93</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">，如不治療則可能致死</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">　</span><span style="color: black; font-size: 11pt;"> Carithers</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">等人曾對</span><span style="color: black; font-size: 11pt;">df</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">的計算法作以下修正：前凝血酵素改為比正常凝血時間延長之秒數，並將血清膽紅素值除以</span><span style="color: black; font-size: 11pt;">17.1</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">以取得</span><span style="color: black; font-size: 11pt;">mmol/L</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">單位，代入上式而計算修正後的</span><span style="color: black; font-size: 11pt;">df</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">值，修正後病人的</span><span style="color: black; font-size: 11pt;">df</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">值大於或等於</span><span style="color: black; font-size: 11pt;">32</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">的病人，則被納入</span><span style="color: black; font-size: 11pt;">methylprednisolone</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">治療試驗（相當於</span><span style="color: black; font-size: 11pt;">Maddrey df</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">值約</span><span style="color: black; font-size: 11pt;">106</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）。</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><b></b></p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">4</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">、</span><span style="color: black; font-size: 11pt;">Mayo</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">對原發型膽汁肝硬化</span><span style="color: black; font-size: 11pt;">(Primary Biliary Cirrhosis)</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">之存活模式</span><b> </b></p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">Mayo</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">存活模式乃基於預測死亡因子的</span><span style="color: black; font-size: 11pt;">Cox</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">正比危害回歸分析（</span><span style="color: black; font-size: 11pt;">Cox proportional hazard regression analyses</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）而得，此複雜的公式採用</span><span style="color: black; font-size: 11pt;">5</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">項最具影響力的變異數計算致死危險性（</span><span style="color: black; font-size: 11pt;">R</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）來預測存活時間</span><span style="color: black; font-size: 11pt;">S</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">（</span><span style="color: black; font-size: 11pt;">t</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">&nbsp;&nbsp; S ( t )</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">＝</span><span style="color: black; font-size: 11pt;">{S<sub>o</sub></span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">（</span><span style="color: black; font-size: 11pt;">t</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）</span><span style="color: black; font-size: 11pt;">}<sup>exp(R-5.07)</sup></span></p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><sup><span style="color: black; font-size: 11pt;">&nbsp;&nbsp;&nbsp; </span></sup><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">其中</span><span style="color: black; font-size: 11pt;">S</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">（</span><span style="color: black; font-size: 11pt;">t</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）即</span><span style="color: black; font-size: 11pt;">t </span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">年的存活機率</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">　</span><span style="color: black; font-size: 11pt;"> R</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">＝</span><span style="color: black; font-size: 11pt;">0.871 ln</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">（</span><span style="color: black; font-size: 11pt;">B</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）＋</span><span style="color: black; font-size: 11pt;">2.53 ln</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">（</span><span style="color: black; font-size: 11pt;">A</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）＋</span><span style="color: black; font-size: 11pt;">0.039</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">（</span><span style="color: black; font-size: 11pt;">Y</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）＋</span><span style="color: black; font-size: 11pt;">0.859</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">（</span><span style="color: black; font-size: 11pt;">E</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）＋</span><span style="color: black; font-size: 11pt;">2.38 ln</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">（</span><span style="color: black; font-size: 11pt;">PT</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">（</span><span style="color: black; font-size: 11pt;">B</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">代表膽紅素，</span><span style="color: black; font-size: 11pt;">mg/dL</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">；</span><span style="color: black; font-size: 11pt;">A</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">代表白蛋白，</span><span style="color: black; font-size: 11pt;">g/dL</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">；</span><span style="color: black; font-size: 11pt;">Y</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">代表年齡；</span><span style="color: black; font-size: 11pt;">E</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">代表水腫；</span><span style="color: black; font-size: 11pt;">PT</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">代表前凝血酵素時間，秒）</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;">&nbsp;</p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">&nbsp;&nbsp; S<sub>o</sub></span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">（</span><span style="color: black; font-size: 11pt;">t</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）值是由</span><span style="color: black; font-size: 11pt;">418</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">位病人所觀察到的存活結果而得之平均危險分數值（假設</span><span style="color: black; font-size: 11pt;">R=5.07</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）：</span> </p><table style="border-collapse: collapse;border: medium none;" border="1" cellspacing="0" cellpadding="0"> <tbody> <tr> <td style="padding-bottom: 0cm; background-color: transparent; padding-left: 1.4pt; width: 52.25pt; padding-right: 1.4pt; padding-top: 0cm;border: windowtext 1pt solid;" valign="top"> <p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">t years</span></p> </td> <td style="border-bottom: windowtext 1pt solid; padding-bottom: 0cm; background-color: transparent; padding-left: 1.4pt; width: 52.25pt; padding-right: 1.4pt; border-left-color: #f0f0f0; border-top: windowtext 1pt solid; border-right: windowtext 1pt solid; padding-top: 0cm;" valign="top"> <p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">1</span></p> </td> <td style="border-bottom: windowtext 1pt solid; padding-bottom: 0cm; background-color: transparent; padding-left: 1.4pt; width: 52.25pt; padding-right: 1.4pt; border-left-color: #f0f0f0; border-top: windowtext 1pt solid; border-right: windowtext 1pt solid; padding-top: 0cm;" valign="top"> <p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">2</span></p> </td> <td style="border-bottom: windowtext 1pt solid; padding-bottom: 0cm; background-color: transparent; padding-left: 1.4pt; width: 52.25pt; padding-right: 1.4pt; border-left-color: #f0f0f0; border-top: windowtext 1pt solid; border-right: windowtext 1pt solid; padding-top: 0cm;" valign="top"> <p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">3</span></p> </td> <td style="border-bottom: windowtext 1pt solid; padding-bottom: 0cm; background-color: transparent; padding-left: 1.4pt; width: 52.25pt; padding-right: 1.4pt; border-left-color: #f0f0f0; border-top: windowtext 1pt solid; border-right: windowtext 1pt solid; padding-top: 0cm;" valign="top"> <p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">4</span></p> </td> <td style="border-bottom: windowtext 1pt solid; padding-bottom: 0cm; background-color: transparent; padding-left: 1.4pt; width: 52.25pt; padding-right: 1.4pt; border-left-color: #f0f0f0; border-top: windowtext 1pt solid; border-right: windowtext 1pt solid; padding-top: 0cm;" valign="top"> <p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">5</span></p> </td> <td style="border-bottom: windowtext 1pt solid; padding-bottom: 0cm; background-color: transparent; padding-left: 1.4pt; width: 52.3pt; padding-right: 1.4pt; border-left-color: #f0f0f0; border-top: windowtext 1pt solid; border-right: windowtext 1pt solid; padding-top: 0cm;" valign="top"> <p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">6</span></p> </td> <td style="border-bottom: windowtext 1pt solid; padding-bottom: 0cm; background-color: transparent; padding-left: 1.4pt; width: 52.3pt; padding-right: 1.4pt; border-left-color: #f0f0f0; border-top: windowtext 1pt solid; border-right: windowtext 1pt solid; padding-top: 0cm;" valign="top"> <p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">7</span></p> </td> </tr> <tr> <td style="border-bottom: windowtext 1pt solid; border-left: windowtext 1pt solid; padding-bottom: 0cm; background-color: transparent; border-top-color: #f0f0f0; padding-left: 1.4pt; width: 52.25pt; padding-right: 1.4pt; border-right: windowtext 1pt solid; padding-top: 0cm;" valign="top"> <p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">S<sub>o</sub></span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">（</span><span style="color: black; font-size: 11pt;">t</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）</span> </p> </td> <td style="border-bottom: windowtext 1pt solid; padding-bottom: 0cm; background-color: transparent; border-top-color: #f0f0f0; padding-left: 1.4pt; width: 52.25pt; padding-right: 1.4pt; border-left-color: #f0f0f0; border-right: windowtext 1pt solid; padding-top: 0cm;" valign="top"> <p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">0.970</span></p> </td> <td style="border-bottom: windowtext 1pt solid; padding-bottom: 0cm; background-color: transparent; border-top-color: #f0f0f0; padding-left: 1.4pt; width: 52.25pt; padding-right: 1.4pt; border-left-color: #f0f0f0; border-right: windowtext 1pt solid; padding-top: 0cm;" valign="top"> <p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">0.941</span></p> </td> <td style="border-bottom: windowtext 1pt solid; padding-bottom: 0cm; background-color: transparent; border-top-color: #f0f0f0; padding-left: 1.4pt; width: 52.25pt; padding-right: 1.4pt; border-left-color: #f0f0f0; border-right: windowtext 1pt solid; padding-top: 0cm;" valign="top"> <p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">0.883</span></p> </td> <td style="border-bottom: windowtext 1pt solid; padding-bottom: 0cm; background-color: transparent; border-top-color: #f0f0f0; padding-left: 1.4pt; width: 52.25pt; padding-right: 1.4pt; border-left-color: #f0f0f0; border-right: windowtext 1pt solid; padding-top: 0cm;" valign="top"> <p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">0.883</span></p> </td> <td style="border-bottom: windowtext 1pt solid; padding-bottom: 0cm; background-color: transparent; border-top-color: #f0f0f0; padding-left: 1.4pt; width: 52.25pt; padding-right: 1.4pt; border-left-color: #f0f0f0; border-right: windowtext 1pt solid; padding-top: 0cm;" valign="top"> <p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">0.774</span></p> </td> <td style="border-bottom: windowtext 1pt solid; padding-bottom: 0cm; background-color: transparent; border-top-color: #f0f0f0; padding-left: 1.4pt; width: 52.3pt; padding-right: 1.4pt; border-left-color: #f0f0f0; border-right: windowtext 1pt solid; padding-top: 0cm;" valign="top"> <p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">0.721</span></p> </td> <td style="border-bottom: windowtext 1pt solid; padding-bottom: 0cm; background-color: transparent; border-top-color: #f0f0f0; padding-left: 1.4pt; width: 52.3pt; padding-right: 1.4pt; border-left-color: #f0f0f0; border-right: windowtext 1pt solid; padding-top: 0cm;" valign="top"> <p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">0.651</span></p> </td> </tr> </tbody></table><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">&nbsp; </span></p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">&nbsp;</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">稍後</span><span style="color: black; font-size: 11pt;">Wiesner</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">等人研究</span><span style="color: black; font-size: 11pt;">174</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">位原發硬化性膽道炎</span><span style="color: black; font-size: 11pt;">(primary sclerosing cholangitis)</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">的病人並發展出另一種分析模式。除年齡及血清膽紅素〈最高採用</span><span style="color: black; font-size: 11pt;">10 mg/dL</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">〉外，此回歸分析法還確認血中血紅素濃度（</span><span style="color: black; font-size: 11pt;">Hb</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">，</span><span style="color: black; font-size: 11pt;">g/dL</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">，在</span><span style="color: black; font-size: 11pt;">12g/dL</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">以下），發炎性腸道疾病（</span><span style="color: black; font-size: 11pt;">IBD</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">：</span><span style="color: black; font-size: 11pt;">1</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">表示有，</span><span style="color: black; font-size: 11pt;">0</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">表示沒有）和組織切片肝纖維化程度（</span><span style="color: black; font-size: 11pt;">S,0</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">到</span><span style="color: black; font-size: 11pt;">4</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）等重要因子：</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;">&nbsp;</p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">R</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">＝</span><span style="color: black; font-size: 11pt;">0.85 ln</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">（</span><span style="color: black; font-size: 11pt;">B</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）＋</span><span style="color: black; font-size: 11pt;">0.06</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">（</span><span style="color: black; font-size: 11pt;">Y</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）－</span><span style="color: black; font-size: 11pt;">4.39 ln</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">（</span><span style="color: black; font-size: 11pt;">Hb</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）＋</span><span style="color: black; font-size: 11pt;">1.59</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">（</span><span style="color: black; font-size: 11pt;">IBD</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）＋</span><span style="color: black; font-size: 11pt;">0.51S</span></p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;">&nbsp;</p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="color: black; font-size: 11pt;">5</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">、</span><span style="color: black; font-size: 11pt;">Monoethylglycinexylidide</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">（</span><span style="color: black; font-size: 11pt;">MEGX</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">）</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;"><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">此一化合物是</span><span style="color: black; font-size: 11pt;">lidocaine</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">經由肝臟</span><span style="color: black; font-size: 11pt;">CYP3A</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">酵素系統代謝後的主要代謝物。在連續</span><span style="color: black; font-size: 11pt;">2</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">分鐘靜脈輸注</span><span style="color: black; font-size: 11pt;">1mg/</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">㎏的</span><span style="color: black; font-size: 11pt;">lidocaine</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">後，測量其</span><span style="color: black; font-size: 11pt;">15</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">、</span><span style="color: black; font-size: 11pt;">30</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">及</span><span style="color: black; font-size: 11pt;">60</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">分鐘時之濃度，其結果與</span><span style="color: black; font-size: 11pt;">Child-Pugh</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">的得分結果有良好的相關性</span><span style="color: black; font-size: 11pt;">(Testa </span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">等</span><span style="color: black; font-size: 11pt;">1997)</span><span style="font-family: 新細明體,serif; color: black; font-size: 11pt;">。</span> </p><p style="text-justify: inter-ideograph; text-align: justify; line-height: 20pt;">&nbsp;</p>
發佈日期 2013-12-04
附件檔案