School of Pharmacy, University of Maryland, Baltimore, MD 21201, USA.
J Clin Pharmacol. 2013 Sep;53(9):962-6. doi: 10.1002/jcph.128. Epub 2013 Jul 7.
Pharmacokinetic (PK) studies in patients with liver disease are an important clinical pharmacology component of drug development. In 2003, FDA released the guidance for industry on "Pharmacokinetics in Patients with Impaired Hepatic Function," which provides recommendations to sponsors on study design, data analysis, and impact on dosing and labeling. We evaluated the quality and consistency of hepatic dosing recommendations, and compared contemporary clinical practice of dosing in patients with impaired hepatic function with product labels. All new molecular entities (NME) and labels approved by the FDA during the period of January 2004 to December 2011 were reviewed. The fraction of the dose hepatically eliminated, quality of hepatic impairment PK studies reported, and any dose recommendations provided in the label and in a tertiary clinical reference (Micromedex) were reviewed. Out of 157 NMEs, 67 met the criteria for evaluation of dosing in hepatic disease. Problem areas were identified related to the lack of specific hepatic metabolism information in 90% of FDA-approved labels, inconsistent terminology, and "use with caution in liver disease" in 27% of NME. Updating the FDA guidance on PK studies in patients with impaired hepatic function could provide a standardized approach to improve the clinical usefulness of this dosing information for practitioners.
肝功能不全患者的药代动力学（PK）研究是药物开发中重要的临床药理学组成部分。2003 年，FDA 发布了《肝功能不全患者的药代动力学》行业指南，为申办者提供了关于研究设计、数据分析以及对剂量调整和标签影响的建议。我们评估了肝剂量推荐的质量和一致性，并比较了当代肝功能不全患者的临床实践与产品标签。对 2004 年 1 月至 2011 年 12 月期间 FDA 批准的所有新分子实体（NME）和标签进行了审查。审查了经肝消除的剂量分数、报告的肝损害 PK 研究的质量以及标签和三级临床参考（Micromedex）中提供的任何剂量建议。在 157 种 NME 中，有 67 种符合评估肝疾病剂量的标准。发现了一些问题，如 90%的 FDA 批准标签中缺乏特定的肝代谢信息、术语不一致，以及 27%的 NME 中使用“肝疾病时慎用”。更新关于肝功能不全患者 PK 研究的 FDA 指南可以为提高该剂量信息对从业者的临床实用性提供一种标准化方法。
