Takeda Development Center Americas, Inc., Lexington, MA, USA.
RES Group Inc., Needham, MA, USA.
J Pharmacokinet Pharmacodyn. 2024 Dec;51(6):721-734. doi: 10.1007/s10928-024-09919-6. Epub 2024 May 11.
Hereditary angioedema (HAE) due to C1-inhibitor deficiency is a rare, debilitating, genetic disorder characterized by recurrent, unpredictable, attacks of edema. The clinical symptoms of HAE arise from excess bradykinin generation due to dysregulation of the plasma kallikrein-kinin system (KKS). A quantitative systems pharmacology (QSP) model that mechanistically describes the KKS and its role in HAE pathophysiology was developed based on HAE attacks being triggered by autoactivation of factor XII (FXII) to activated FXII (FXIIa), resulting in kallikrein production from prekallikrein. A base pharmacodynamic model was constructed and parameterized from literature data and ex vivo assays measuring inhibition of kallikrein activity in plasma of HAE patients or healthy volunteers who received lanadelumab. HAE attacks were simulated using a virtual patient population, with attacks recorded when systemic bradykinin levels exceeded 20 pM. The model was validated by comparing the simulations to observations from lanadelumab and plasma-derived C1-inhibitor clinical trials. The model was then applied to analyze the impact of nonadherence to a daily oral preventive therapy; simulations showed a correlation between the number of missed doses per month and reduced drug effectiveness. The impact of reducing lanadelumab dosing frequency from 300 mg every 2 weeks (Q2W) to every 4 weeks (Q4W) was also examined and showed that while attack rates with Q4W dosing were substantially reduced, the extent of reduction was greater with Q2W dosing. Overall, the QSP model showed good agreement with clinical data and could be used for hypothesis testing and outcome predictions.
遗传性血管性水肿（HAE）是一种罕见的、使人虚弱的遗传性疾病，其特征是反复发作、不可预测的水肿发作。HAE 的临床症状是由于血浆激肽释放酶-激肽系统（KKS）失调导致缓激肽生成过多引起的。基于 XII 因子（FXII）的自身激活触发 HAE 发作，导致激肽原产生激肽，从而建立了一种机械描述 KKS 及其在 HAE 病理生理学中作用的定量系统药理学（QSP）模型。构建了一个基本药效动力学模型，并根据文献数据和测量 HAE 患者或接受拉那芦单抗的健康志愿者血浆中激肽酶活性抑制的离体测定进行参数化。使用虚拟患者群体模拟 HAE 发作，当全身缓激肽水平超过 20 pM 时记录发作。通过将模拟与拉那芦单抗和血浆衍生的 C1 抑制剂临床试验的观察结果进行比较来验证模型。然后将该模型应用于分析不遵守每日口服预防治疗的影响；模拟显示每月错过剂量的次数与药物效果降低之间存在相关性。还检查了将拉那芦单抗给药频率从每 2 周（Q2W）300mg 减少至每 4 周（Q4W）的影响，结果表明，尽管 Q4W 给药的发作率大大降低，但 Q2W 给药的降低幅度更大。总体而言，QSP 模型与临床数据具有良好的一致性，可用于假设检验和结果预测。
