Baldrick Paul
Scientific and Regulatory Consulting, Covance Laboratories Ltd., Otley Road, Harrogate, North Yorkshire HG3 1PY, England, UK.
Regul Toxicol Pharmacol. 2008 Jul;51(2):237-43. doi: 10.1016/j.yrtph.2008.04.006. Epub 2008 May 22.
Toxicology (single dose, range-finding, repeat dose and genotoxicity) data available in 34 Investigator's Brochures used to support First-In-Man clinical trials over a 10 year period have been evaluated to give an insight into the types of study designs used and how these have changed over the period analysed (1997-2006). Study packages had single dose toxicity studies in the rodent (although there has been a recent trend to reduce the number of these studies), range-finding toxicity studies in the rodent and non-rodent (with only small numbers of the latter used) and key 2- 4 week repeat dose toxicity studies in rodent (usually rat) and non-rodent (both dog and monkey). The majority of the latter studies established No Observed Adverse Effect Levels, showed the rodent to be generally less sensitive to target organ toxicity than the non-rodent and showed the liver and then the kidney to be the most common target organs. Genotoxicity assessment included 2 in vitro assays (a reverse mutation bacteria and either a chromosome aberration or mouse lymphoma assay) and commonly, an in vivo rodent bone marrow micronucleus test. Considerations for general toxicology and genotoxicity study designs are discussed along with the use of appropriate information to help set the clinical starting dose.
对34份研究者手册中的毒理学（单剂量、剂量范围查找、重复剂量和遗传毒性）数据进行了评估，这些手册用于支持为期10年的首次人体临床试验，以便深入了解所采用的研究设计类型以及在分析期间（1997 - 2006年）这些设计是如何变化的。研究包包括啮齿动物的单剂量毒性研究（尽管最近有减少此类研究数量的趋势）、啮齿动物和非啮齿动物的剂量范围查找毒性研究（后者使用数量较少）以及啮齿动物（通常是大鼠）和非啮齿动物（狗和猴子）的关键2 - 4周重复剂量毒性研究。大多数后者的研究确定了未观察到不良反应水平，表明啮齿动物对靶器官毒性的敏感性通常低于非啮齿动物，并表明肝脏是最常见的靶器官，其次是肾脏。遗传毒性评估包括2种体外试验（一种回复突变细菌试验和一种染色体畸变或小鼠淋巴瘤试验），通常还包括一项体内啮齿动物骨髓微核试验。讨论了一般毒理学和遗传毒性研究设计的考虑因素以及如何使用适当信息来帮助确定临床起始剂量。
