Simcyp Limited, Sheffield, UK.
Clin Pharmacokinet. 2010 Mar;49(3):189-206. doi: 10.2165/11318160-000000000-00000.
Liver cirrhosis is characterized by a decrease in functional hepatocytes, lowered circulating levels of plasma proteins and alterations in blood flow due to the development of portacaval shunts. Depending on the interplay between these parameters and the characteristics of an administered drug, varying degrees of impaired systemic clearance and first-pass metabolism are anticipated. The Simcyp Population-based ADME Simulator has already been used successfully to incorporate genetic, physiological and demographic attributes of certain subgroups within healthy populations into in vitro-in vivo extrapolation (IVIVE) of xenobiotic clearance. The objective of this study was to extend population models to predict systemic and oral drug clearance in relation to the severity of liver cirrhosis.
Information on demographics, changes in hepatic blood flow, cytochrome P450 enzymes, liver size, plasma protein binding and renal function was incorporated into three separate population libraries. The latter corresponded to Child-Pugh scores A (mild), B (moderate) and C (severe) liver cirrhosis. These libraries, together with mechanistic IVIVE within the Simcyp Simulator, were used to predict the clearance of intravenous and oral midazolam, oral caffeine, intravenous and oral theophylline, intravenous and oral metoprolol, oral nifedipine, oral quinidine, oral diclofenac, oral sildenafil, and intravenous and oral omeprazole. The simulated patients matched the clinical studies as closely as possible with regard to demographics and Child-Pugh scores. Predicted clearance values in both healthy control and liver cirrhosis populations were compared with observed values, as were the fold increases in clearance values between these populations.
There was good agreement (lack of statistically significant difference, two-tailed paired t-test) between observed and predicted clearance ratios, with the exception of those for two studies of intravenous omeprazole. Predicted clearance ratios were within 0.8- to 1.25-fold of observed ratios in 65% of cases (range 0.34- to 2.5-fold).
The various drugs that were studied showed different changes in clearance in relation to disease severity, and a 'one size fits all' solution does not exist without considering the multiple sources of the changes. Predictions of the effects of liver cirrhosis on drug clearance are of potential value in the design of clinical studies during drug development and, clinically, in the assessment of likely dosage adjustment.
肝硬化的特征是功能性肝细胞减少，循环血浆蛋白水平降低，以及由于门腔分流的发展而导致血流改变。根据这些参数之间的相互作用以及给予药物的特性，可以预期会出现不同程度的全身清除率受损和首过代谢。Simcyp 基于人群的 ADME 模拟器已经成功地将特定健康人群亚组的遗传、生理和人口统计学特征纳入外源性物质清除的体外-体内外推（IVIVE）。本研究的目的是扩展人群模型，以预测与肝硬化严重程度相关的全身和口服药物清除率。
将人口统计学、肝血流变化、细胞色素 P450 酶、肝大小、血浆蛋白结合和肾功能等信息纳入三个单独的人群库中。后者对应于 Child-Pugh 评分 A（轻度）、B（中度）和 C（重度）肝硬化。这些库与 Simcyp 模拟器中的机制 IVIVE 一起，用于预测咪达唑仑静脉和口服、咖啡因口服、茶碱静脉和口服、美托洛尔静脉和口服、硝苯地平口服、奎尼丁口服、双氯芬酸口服、西地那非口服和奥美拉唑静脉和口服的清除率。模拟患者在人口统计学和 Child-Pugh 评分方面尽可能与临床研究相匹配。比较了健康对照组和肝硬化人群的预测清除值与观察值，以及这些人群之间清除值的倍数增加。
除了两项奥美拉唑静脉注射研究外，观察到的和预测的清除率比值之间存在良好的一致性（无统计学意义差异，双侧配对 t 检验）。在 65%的情况下（范围为 0.34 至 2.5 倍），预测清除率比值在观察到的比值的 0.8 至 1.25 倍范围内。
研究的各种药物在清除率方面表现出与疾病严重程度相关的不同变化，并且如果不考虑多种变化来源，就不存在“一刀切”的解决方案。预测肝硬化对药物清除率的影响对于药物开发过程中临床研究的设计以及临床评估可能的剂量调整具有潜在价值。
