Chorus, Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, Indiana, USA.
CPT Pharmacometrics Syst Pharmacol. 2013 Aug 21;2(8):e66. doi: 10.1038/psp.2013.43.
LY2878735 is a novel dual serotonin (5-hydroxytryptamine (5-HT)) and norepinephrine (NE) reuptake inhibitor (SNRI) in development for chronic pain indications. In vitro profile suggests a more balanced profile as compared with other SNRI's, which is expected to confer superior clinical efficacy. LY2878735 is metabolized partly by the genetically polymorphic cytochrome P450 (CYP) 2D6 pathway, raising pharmacokinetic (PK) variability concerns. Phase 1 PK and biomarker data were analyzed by pharmacometric methods to characterize the balance between dual-target engagement and adverse effects on heart rate (HR) and blood pressure (BP). A narrow range of plasma LY2878735 levels was associated with an acceptable balance. As compared with poor metabolizers (PM), CYP2D6 extensive metabolizers (EM) have 21- and threefold higher clearance and distribution volume, respectively. Even with a CYP2D6-based dosing paradigm, a superior therapeutic index comparable to duloxetine, a widely used SNRI, was not achievable and LY2878735 development was thus terminated. Model-based approach effectively synthesizes PK-pharmacodynamic (PD) relationships, enabling efficient early development decisions.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e66; doi:10.1038/psp.2013.43; published online 21 August 2013.
LY2878735 是一种新型的双重 5-羟色胺（5-HT）和去甲肾上腺素（NE）再摄取抑制剂（SNRI），用于治疗慢性疼痛适应症。体外研究表明，与其他 SNRI 相比，其具有更平衡的特征，有望带来更优异的临床疗效。LY2878735 部分通过遗传多态性细胞色素 P450（CYP）2D6 途径代谢，从而引发了药代动力学（PK）变异性的担忧。通过药代动力学方法分析了 I 期 PK 和生物标志物数据，以描述双重靶标占有率与心率（HR）和血压（BP）不良反应之间的平衡关系。研究发现，LY2878735 的血浆水平范围较窄与可接受的平衡有关。与弱代谢者（PM）相比，CYP2D6 广泛代谢者（EM）的清除率和分布容积分别高 21 倍和 3 倍。即使采用基于 CYP2D6 的剂量方案，也无法达到与度洛西汀（一种广泛使用的 SNRI）相当的优异治疗指数，因此终止了 LY2878735 的开发。基于模型的方法可有效综合药代动力学-药效学（PD）关系，从而能够为早期开发决策提供高效支持。CPT：药理学与系统药理学（2013 年）2，e66；doi：10.1038/psp.2013.43；在线发表于 2013 年 8 月 21 日。
