Fepixnebart（LY3016859）和表皮调节素在慢性疼痛患者中的群体药代动力学和药效学
Population Pharmacokinetics and Pharmacodynamics of Fepixnebart (LY3016859) and Epiregulin in Patients with Chronic Pain.
作者信息
James Douglas E, Bailey Jason, van der Walt Jan-Stefan, Winkler Julia, Schoemaker Rik
机构信息
Global PK/PD and Pharmacometrics, Eli Lilly and Company Corporate Center, Indianapolis, IN, 46285, USA.
LEM CAG, Eli Lilly and Company, Indianapolis, IN, USA.
出版信息
Clin Pharmacokinet. 2025 May;64(5):757-767. doi: 10.1007/s40262-025-01506-3. Epub 2025 Apr 23.
BACKGROUND AND OBJECTIVE
Fepixnebart (LY3016859), a humanized immunoglobulin G4 monoclonal antibody with high binding affinity to epiregulin and tumor growth factor-α, is being developed as a novel analgesic to treat broad-spectrum chronic pain. Early phase clinical studies demonstrated fepixnebart has nonlinear pharmacokinetics in healthy subjects and patients with diabetic nephropathy. This population pharmacokinetic analysis used data from three 26-week, phase 2, proof-of-concept studies in osteoarthritis, diabetic peripheral neuropathic pain (DPNP), and chronic low back pain (CLBP) to characterize the pharmacokinetics of fepixnebart and predict its target engagement by epiregulin. Covariate relationships were also assessed.
METHODS
Population analysis was performed using nonlinear mixed-effects modeling software. Covariate relationships were explored graphically by plotting potential covariates versus parameters of interest. Simulated target engagement was predicted using the phase 2 dose regimen for fepixnebart (750 mg intravenous starting dose, followed by 500 mg every 2 weeks).
RESULTS
The median simulated target engagement at 2 weeks after the last dose of fepixnebart was predicted to be 92.0%, with 90% of predictions between 86.0 and 96.2% and 68.5% of subjects predicted to exhibit target engagement exceeding 90%.
CONCLUSIONS
The phase 2 dose regimen is adequate to test the analgesic effect of fepixnebart in patients with osteoarthritis, DPNP, and CLBP. In the final model, female sex and higher glomerular filtration rate were associated with higher clearance, female sex was associated with larger volume of distribution of the central compartment (V) than male sex, and DPNP was associated with lower V than CLBP. There were no significant effects on the concentration of fepixnebart at which its effect on epiregulin is half-maximal (EC).
TRAIL REGISTRY
ClinicalTrials.gov: NCT04529096, NCT04476108, and NCT04456686.
背景与目的
Fepixnebart（LY3016859）是一种对表皮调节素和肿瘤生长因子-α具有高结合亲和力的人源化免疫球蛋白G4单克隆抗体，正作为一种新型镇痛药用于治疗广谱慢性疼痛。早期临床研究表明，Fepixnebart在健康受试者和糖尿病肾病患者中具有非线性药代动力学。这项群体药代动力学分析使用了来自三项为期26周的2期概念验证研究的数据，这些研究分别针对骨关节炎、糖尿病周围神经病理性疼痛（DPNP）和慢性下腰痛（CLBP），以表征Fepixnebart的药代动力学，并预测其与表皮调节素的靶点结合情况。还评估了协变量关系。
方法
使用非线性混合效应建模软件进行群体分析。通过绘制潜在协变量与感兴趣参数的关系图，以图形方式探索协变量关系。使用Fepixnebart的2期剂量方案（静脉注射起始剂量750mg，随后每2周注射500mg）预测模拟靶点结合情况。
结果
在最后一剂Fepixnebart后2周，模拟靶点结合的中位数预计为92.0%，90%的预测值在86.0%至96.2%之间，68.5%的受试者预计靶点结合超过90%。
结论
2期剂量方案足以测试Fepixnebart对骨关节炎、DPNP和CLBP患者的镇痛效果。在最终模型中，女性和较高的肾小球滤过率与较高的清除率相关，女性与男性相比，中央室分布容积（V）更大，DPNP与CLBP相比，V更低。对Fepixnebart对表皮调节素产生半数最大效应时的浓度（EC）没有显著影响。
试验注册
ClinicalTrials.gov：NCT04529096、NCT04476108和NCT04456686。
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