Real World Evidence Platform, Pfizer, Inc., New York, NY, USA.
Internal Medicine Research Unit, Pfizer, Inc., New York, NY, USA.
Clin Transl Sci. 2024 Mar;17(3):e13741. doi: 10.1111/cts.13741.
Drug development teams must evaluate the risk/benefit profile of new drug candidates that perpetrate drug-drug interactions (DDIs). Real-world data (RWD) can inform this decision. The purpose of this study was to develop a predicted impact score for DDIs perpetrated by three hypothetical drug candidates via CYP3A, CYP2D6, or CYP2C9 in type 2 diabetes mellitus (T2DM), obesity, or migraine. Optum Market Clarity was analyzed to estimate use of CYP3A, CYP2D6, or CYP2C9 substrates classified in the University of Washington Drug Interaction Database as moderate sensitive, sensitive, narrow therapeutic index, or QT prolongation. Scoring was based on prevalence of exposure to victim substrates and characteristics (age, polypharmacy, duration of exposure, and number of prescribers) of those exposed. The study population of 14,163,271 adults included 1,579,054 with T2DM, 3,117,753 with obesity, and 410,436 with migraine. For T2DM, 71.3% used CYP3A substrates, 44.3% used CYP2D6 substrates, and 44.3% used CYP2C9 substrates. For obesity, 57.1% used CYP3A substrates, 34.6% used CYP2D6 substrates, and 31.0% used CYP2C9 substrates. For migraine, 64.1% used CYP3A substrates, 44.0% used CYP2D6 substrates, and 28.9% used CYP2C9 substrates. In our analyses, the predicted DDI impact scores were highest for DDIs involving CYP3A, followed by CYP2D6, and CYP2C9 substrates, and highest for T2DM, followed by migraine, and obesity. Insights from RWD can be used to estimate a predicted DDI impact score for pharmacokinetic DDIs perpetrated by new drug candidates currently in development. This score can inform the risk/benefit profile of new drug candidates in a target patient population.
药物开发团队必须评估新候选药物引发的药物-药物相互作用（DDI）的风险/收益情况。真实世界数据（RWD）可以为此决策提供信息。本研究的目的是开发一个预测评分，用于评估三种假设的候选药物通过 CYP3A、CYP2D6 或 CYP2C9 对 2 型糖尿病（T2DM）、肥胖症或偏头痛患者引发 DDI 的影响。分析 Optum Market Clarity 以估计 CYP3A、CYP2D6 或 CYP2C9 底物的使用情况，这些底物被归类为华盛顿大学药物相互作用数据库中的中度敏感、敏感、窄治疗指数或 QT 延长。评分基于暴露于易受影响底物的患者的流行程度以及暴露患者的特征（年龄、多药治疗、暴露持续时间和开处方者数量）。研究人群包括 14163271 名成年人，其中 1579054 人患有 T2DM、3117753 人患有肥胖症和 410436 人患有偏头痛。对于 T2DM，71.3%的患者使用 CYP3A 底物，44.3%的患者使用 CYP2D6 底物，44.3%的患者使用 CYP2C9 底物。对于肥胖症，57.1%的患者使用 CYP3A 底物，34.6%的患者使用 CYP2D6 底物，31.0%的患者使用 CYP2C9 底物。对于偏头痛，64.1%的患者使用 CYP3A 底物，44.0%的患者使用 CYP2D6 底物，28.9%的患者使用 CYP2C9 底物。在我们的分析中，涉及 CYP3A 的 DDI 影响预测评分最高，其次是 CYP2D6 和 CYP2C9 底物，对于 T2DM 的影响评分最高，其次是偏头痛，最后是肥胖症。真实世界数据的见解可用于估计当前开发的新药候选物引发的药物代谢动力学 DDI 的预测 DDI 影响评分。该评分可以为目标患者人群中的新药候选物的风险/收益情况提供信息。
