Tortorici Michael A, Cutler David L, Hazra Anasuya, Nolin Thomas D, Rowland-Yeo Karen, Venkatakrishnan Karthik
CSL Behring, King of Prussia, PA, USA.
Merck & Co., Upper Whales, PA, USA.
J Clin Pharmacol. 2015 Mar;55(3):241-50. doi: 10.1002/jcph.444. Epub 2015 Jan 14.
Chronic kidney disease (CKD) has been shown to alter the pharmacokinetics of drugs that are eliminated not only via the renal pathway but also by nonrenal clearance and transport. Dosing recommendations in subjects with CKD have historically come from small pharmacokinetic (PK) studies, which have been insulated from the broader clinical development strategy. Opportunities for prospective strategic integration of both preclinical and clinical data on drug clearance mechanisms, model-based approaches, and clinical knowledge of therapeutic index are therefore often missed in designing and analyzing the results of PK studies in subjects with CKD, and eventually providing dosing recommendations. These considerations are valuable in designing informative PK studies in subjects with CKD, as well as for guiding kidney function-related inclusion/exclusion criteria in the broader clinical program and ultimately defining dosing guidelines that optimize benefit-risk balance for these special patient populations based on all available data. This paper offers points to consider for drug developers to increase adoption of a contemporary multidisciplinary approach, which includes key considerations on study design and conduct, methodologies for analysis (population PK and physiologically based PK modeling), and a roadmap to interpret the effect of kidney function on the overall benefit-risk profile of drugs in development.
慢性肾脏病（CKD）已被证明会改变药物的药代动力学，这些药物不仅通过肾脏途径消除，还通过非肾脏清除和转运消除。历史上，针对CKD患者的给药建议来自小型药代动力学（PK）研究，这些研究与更广泛的临床开发策略脱节。因此，在设计和分析CKD患者的PK研究结果并最终提供给药建议时，常常错过将临床前和临床数据在药物清除机制、基于模型的方法以及治疗指数的临床知识方面进行前瞻性战略整合的机会。这些考量对于设计针对CKD患者的信息丰富的PK研究很有价值，对于在更广泛的临床项目中指导与肾功能相关的纳入/排除标准，以及最终根据所有可用数据定义优化这些特殊患者群体的获益-风险平衡的给药指南也很有价值。本文为药物研发人员提供了一些要点以供参考，以增加采用当代多学科方法，其中包括关于研究设计与实施的关键考量、分析方法（群体PK和基于生理的PK建模），以及解读肾功能对正在研发药物的整体获益-风险概况影响的路线图。
