Using Human 'Experiments of Nature' to Predict Drug Safety Issues: An Example with PCSK9 Inhibitors.
Using Human 'Experiments of Nature' to Predict Drug Safety Issues: An Example with PCSK9 Inhibitors.
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DOI：
10.1007/s40264-017-0616-0
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发表时间：
2018-03
期刊：
影响因子：
4.2
通讯作者：
Denny JC
中科院分区：
文献类型：
--
作者：
Jerome RN;Pulley JM;Roden DM;Shirey-Rice JK;Bastarache LA;R Bernard G;B Ekstrom L;Lancaster WJ;Denny JC
当一种新药进入市场时，其全部副作用仍有待确定。目前针对这些影响的监测方法在很大程度上仍然是被动的。需要开发方法来预测特定的安全性事件，这些安全性事件应在开发和上市后活动期间针对给定的新药进行寻找。我们在这里提出了一种安全信号识别方法，适用于一组新的药物实体，丝氨酸蛋白酶前蛋白转化酶枯草杆菌蛋白酶/kexin 9型（PCSK 9）的抑制剂。使用全表型关联研究（PheWAS）方法，我们分析了来自29，722例患者的可用基因型和临床数据，利用PCSK 9变化的已知影响来确定这种蛋白质及其抑制剂可能产生影响的新表型。PheWAS显示高胆固醇血症的风险显著降低（OR 0.68，p=7.6 × 10−4），与PCSK 9中已知的功能丧失变体R46 L相关。同样，实验室数据表明携带R46 L变异体的个体的β平均LDL-C显著降低（−14.47 mg/dl，p=2.58×10−23）。R46 L变异也与脊柱裂风险增加相关（OR 5.90，p=2.7 × 10−4），这表明可能需要进一步研究PCSK 9抑制与神经管缺陷之间的潜在联系。这种新的方法提供了一个机会，可以建立新的机制来评估PCSK 9抑制剂和其他新药物的安全性和长期耐受性，因为它们进入人体测试和扩大临床使用。
When a new drug enters the market, its full array of side effects remains to be defined. Current surveillance approaches targeting these effects remain largely reactive. There is a need for development of methods to predict specific safety events that should be sought for a given new drug during development and post-marketing activities. We present here a safety signal identification approach applied to a new set of drug entities, inhibitors of the serine protease proprotein convertase subtilisin/kexin type 9 (PCSK9). Using phenome-wide association study (PheWAS) methods, we analyzed available genotype and clinical data from 29,722 patients, leveraging the known effects of changes in PCSK9 to identify novel phenotypes in which this protein and its inhibitors may have impact. PheWAS revealed significantly reduced risk of hypercholesterolemia (OR 0.68, p=7.6 × 10−4) in association with a known loss-of-function variant in PCSK9, R46L. Similarly, laboratory data indicated significantly reduced beta mean LDL-C (−14.47 mg/dl, p=2.58×10−23) in individuals carrying the R46L variant. The R46L variant was also associated with increased risk of spina bifida (OR 5.90, p=2.7 × 10−4), suggesting that further investigation of potential connections between inhibition of PCSK9 and neural tube defects may be warranted. This novel methodology provides an opportunity to put in place new mechanisms to assess the safety and long-term tolerability of PCSK9 inhibitors specifically and other new agents, in general, as they move into human testing and expanded clinical use.
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影响因子：
4.7
作者：
Poirier, Steve;Prat, Annik;Seidah, Nabil G.
通讯作者：
Seidah, Nabil G.
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作者：
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通讯作者：
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作者：
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通讯作者：
Roden, D. M.