Pharmetheus AB, Uppsala, Sweden.
Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA.
CPT Pharmacometrics Syst Pharmacol. 2023 Jun;12(6):758-769. doi: 10.1002/psp4.12948. Epub 2023 May 1.
BI 730357 is investigated as an oral treatment of plaque psoriasis. We analyzed the impact of three dosage regimens on the Psoriasis Area and Severity Index (PASI) response with modeling based on phase I and II data from 109 healthy subjects and 274 patients with moderate-to-severe plaque psoriasis. The pharmacokinetics (PK) was characterized by a two-compartment model with dual absorption paths and a first-order elimination. Higher baseline C-reactive protein was associated with lower clearance and patients generally had lower clearance compared with healthy subjects. A bounded integer PK/pharmacodynamic model characterized the effect on the observed PASI. The maximum drug effect was largest for patients with no prior biologic use, smaller for patients with prior use of non-interleukin-17 inhibitors, and smallest for patients with prior interleukin-17 inhibitor use. The models allowed robust simulation of large patient populations, predicting a plateau in PASI outcomes for BI 730357 exposure above 2000 nmol/L.
BI 730357 正在被研究作为斑块状银屑病的口服治疗药物。我们分析了三种剂量方案对基于 109 名健康受试者和 274 名中重度斑块状银屑病患者的 I 期和 II 期数据的建模的银屑病面积和严重程度指数（PASI）应答的影响。药代动力学（PK）的特征是具有双重吸收途径和一级消除的双室模型。较高的基线 C 反应蛋白与较低的清除率相关，与健康受试者相比，患者通常具有较低的清除率。观察到的 PASI 的药效学/药效学模型描述了药物的作用。对于没有先前使用生物制剂的患者，最大药物效应最大，对于先前使用非白细胞介素-17 抑制剂的患者，最大药物效应较小，对于先前使用白细胞介素-17 抑制剂的患者，最大药物效应最小。这些模型允许对大量患者群体进行稳健模拟，预测 BI 730357 暴露量高于 2000nmol/L 时 PASI 结果的平台期。
