Abstract：
Dose selection for investigations of intrinsic and extrinsic factors of pharmacokinetic variability as well as safety is a challenging question in the early clinical stage of drug development. The dose of an investigational product is chosen considering the compound information available to date, feasibility of the assessments, regulatory requirements, and the intent to maximize information for later regulatory submission. This review selected 37 programs as case examples of recently approved drugs to explore the doses selected with focus on studies of drug interaction, renal and hepatic impairment, food effect and concentration-QTc assessment.The review found that regulatory agencies may consider alternative approaches if justified and safe as illustrated in these examples. It is thus recommendable to use the first in human trial as an opportunity to assess QT-prolongation and drug interactions using probes or endogenous markers while maximizing the DDI potential, increasing sensitivity and ensuring safety. Early understanding of dose proportionality assists dose finding and simple and fast to conduct DDI study designs are advantageous. Single dose impairment studies despite non-proportional/time-dependent PK are often acceptability.Overall, the early understanding of the drug\'s safety profile is essential to ensure the safety of doses selected while preventing clinical trials with unnecessary exposure when using high doses or multiple doses. The information collected in this retrospective survey is a good reminder to tailor the early clinical program to the profile and needs of the molecule and consider regulatory opportunities to streamline the development path.
摘要：
在药物开发的早期临床阶段，研究药代动力学变异性的内在和外在因素以及安全性的剂量选择是一个具有挑战性的问题。研究产品的剂量选择考虑到迄今为止可用的化合物信息，评估的可行性，监管要求,以及最大化信息以供以后提交监管文件的意图。这篇综述选择了37个项目作为最近批准的药物的案例，以探索药物相互作用研究中选择的剂量。肾和肝损害，食物效应和浓度-QTc评估。审查发现，如这些示例所示，如果合理且安全，监管机构可以考虑其他方法。因此，建议使用第一个人体试验作为使用探针或内源性标志物评估QT延长和药物相互作用的机会，同时最大化DDI潜力。提高灵敏度，确保安全。对剂量比例性的早期理解有助于剂量发现,并且简单且快速地进行DDI研究设计是有利的。尽管存在非比例/时间依赖性PK，但单剂量损害研究通常是可接受的。总的来说,早期了解药物的安全性对于确保所选剂量的安全性至关重要，同时防止在使用高剂量或多剂量时进行不必要暴露的临床试验。在这项回顾性调查中收集的信息很好地提醒人们，要根据分子的概况和需求量身定制早期临床计划，并考虑监管机会以简化开发路径。
