Roses A D, Saunders A M, Huang Y, Strum J, Weisgraber K H, Mahley R W
Genetics Research, GlaxoSmithKline Research and Development, NC 27709, USA.
Pharmacogenomics J. 2007 Feb;7(1):10-28. doi: 10.1038/sj.tpj.6500397. Epub 2006 Jun 13.
Safety and efficacy pharmacogenetics can be applied successfully to the drug discovery and development pipeline at multiple phases. We review drug-target screening using high throughput SNP associations with complex diseases testing more than 1,800 candidate targets with approximately 7,000 SNPs. Alzheimer's disease data are provided as an example. The supplementation of target-selected screening with genome-wide SNP association, to also define susceptibility genes and relevant disease pathways for human diseases, is discussed. Applications for determining predictive genetic or genomic profiles, or derived biomarkers, for drug efficacy and safety during clinical development are exemplified by several successful experiments at different phases of development. A Phase I-IIA study of side effects using an oral drug for the treatment of breast cancer is used as an example of early pipeline pharmacogenetics to predict side effects and allow optimization of dosing. References are provided for several other recently published genetic association studies of adverse events during drug development. We illustrate the early identification of gene variant candidates related to efficacy in a Phase IIA obesity drug trial to generate hypotheses for testing in subsequent development. How these genetic data generated in Phase IIA are subsequently incorporated as hypotheses into later Phase clinical protocols is discussed. A Phase IIB clinical trial for Alzheimer's disease is described that exemplifies the major pipeline decision between program attrition and further clinical development. In this case, there was no significant improvement in 511 intention-to-treat patients but, applying a confirmed prognostic biomarker (APOE4) to segment the clinical trial population, all three doses of rosiglitazone demonstrated improvement in patients who did not carry the APOE4 allele. The data for the APOE4 carriers demonstrated no significant improvement but suggested that there may be a need for higher doses. Thus, a development program that would have been terminated progressed to Phase III registration trials based on the results of prospective efficacy pharmacogenetic analyses. The implications of using APOE genotype as a biomarker to predict efficacy and possibly dose, as well as supporting the basic neurobiology and pharmacology that provided the original target validation, is discussed. Citations are provided that support a slow neurotoxic effect over many years of a specific fragment of apoE protein (over-produced by apoE4 substrate compared to apoE3) on mitochondria and the use of rosiglitazone to increase mitochondrial biogenesis and improve glucose utilization. Pharmacogenetics is currently being used across the pipeline to prevent attrition and to create safer and more effective medicines.
安全性和有效性药物遗传学可在多个阶段成功应用于药物研发流程。我们回顾了利用高通量单核苷酸多态性（SNP）与复杂疾病的关联进行药物靶点筛选的情况，对1800多个候选靶点和大约7000个SNP进行了检测。以阿尔茨海默病数据为例。讨论了在靶点选择筛选的基础上补充全基因组SNP关联研究，以确定人类疾病的易感基因和相关疾病途径。在临床开发过程中，通过不同阶段的几个成功实验举例说明了确定药物疗效和安全性的预测性遗传或基因组图谱或衍生生物标志物的应用。一项使用口服药物治疗乳腺癌的I-IIA期副作用研究被用作早期研发流程药物遗传学预测副作用并优化给药剂量的示例。还提供了其他几项近期发表的关于药物开发过程中不良事件的遗传关联研究的参考文献。我们阐述了在一项IIA期肥胖症药物试验中早期识别与疗效相关的基因变异候选物，以便为后续开发生成待检验的假设。讨论了如何将在IIA期产生的这些遗传数据作为假设纳入后期的临床方案。描述了一项针对阿尔茨海默病的IIB期临床试验，该试验例证了在项目淘汰和进一步临床开发之间的主要研发流程决策。在这种情况下，511名意向性治疗患者没有显著改善，但应用一个已确认的预后生物标志物（APOE4）对临床试验人群进行分层后，罗格列酮的所有三个剂量在未携带APOE4等位基因的患者中均显示出改善。APOE4携带者的数据没有显著改善，但表明可能需要更高剂量。因此，一个原本会终止的开发项目基于前瞻性疗效药物遗传学分析的结果进入了III期注册试验。讨论了使用APOE基因型作为生物标志物来预测疗效和可能的剂量的意义，以及支持最初靶点验证的基础神经生物学和药理学。提供了参考文献，支持载脂蛋白E（apoE）蛋白的一个特定片段（与apoE3相比，apoE4底物过度产生）对线粒体具有多年的缓慢神经毒性作用，以及使用罗格列酮来增加线粒体生物合成和改善葡萄糖利用。目前，药物遗传学正在整个研发流程中用于防止淘汰，并创造更安全、更有效的药物。
