Dept. of Medical Oncology, Erasmus MC Cancer Institute, Erasmus MC, Rotterdam, the Netherlands.
Dept. of Medical Oncology, Erasmus MC Cancer Institute, Erasmus MC, Rotterdam, the Netherlands.
Biomed Pharmacother. 2024 Oct;179:117341. doi: 10.1016/j.biopha.2024.117341. Epub 2024 Aug 26.
Nintedanib is used to treat both idiopathic and progressive pulmonary fibrosis (IPF/PPF). Evidence of both an exposure-response relationship and an exposure-toxicity relationship has been found, suggesting the potential value of therapeutic drug monitoring (TDM). We aimed to define the therapeutic window of nintedanib in a real-world cohort.
Data from two clinical studies were pooled for this analysis. To quantify exposure to nintedanib, a population-pharmacokinetic (PK) model was developed. Associations between PK and decline in forced vital capacity (FVC) and diffusing capacity (DLCO) were performed using linear-mixed-effect models (LMEM). The exposure-toxicity relationship was evaluated using a Cox proportional hazards model.
In total, 911 PK samples from 99 patients were used to develop the PK model. The LMEM with random slopes and intercepts included 517 pulmonary function tests (PFT) from 81 patients. The average administered nintedanib dose was associated with the rate of FVC decline (p=0.002). Per 50 mg decrease of daily dosage, the rate of FVC decline increased by 53.5 mL/year. Neither nintedanib exposure nor dose significantly affected DLCO decline and they were also not significantly associated with the occurrence of a dose-limiting toxicity (DLT). This may be explained by a large inter- and intrapatient variability in nintedanib PK.
Nintedanib dose was significantly associated with FVC loss. However, no significant relationship between nintedanib exposure and the occurrence of DLTs was found in this real-world population, and no therapeutic window could be established. The findings in this study indicate that nintedanib is an unsuitable candidate for performing TDM.
尼达尼布用于治疗特发性和进行性肺纤维化（IPF/PPF）。已发现尼达尼布的暴露-反应关系和暴露-毒性关系的证据，这表明治疗药物监测（TDM）具有潜在价值。我们旨在定义尼达尼布在真实世界队列中的治疗窗。
本分析汇总了两项临床研究的数据。为了量化尼达尼布的暴露情况，开发了群体药代动力学（PK）模型。使用线性混合效应模型（LMEM）对 PK 与用力肺活量（FVC）和弥散量（DLCO）下降之间的关系进行了关联。使用 Cox 比例风险模型评估了暴露-毒性关系。
共使用 99 名患者的 911 个 PK 样本来开发 PK 模型。LMEM 包括 81 名患者的 517 项肺功能测试（PFT），具有随机斜率和截距。平均给予的尼达尼布剂量与 FVC 下降率相关（p=0.002）。每日剂量减少 50mg，FVC 下降率增加 53.5mL/年。尼达尼布暴露或剂量均与 DLCO 下降无关，也与剂量限制毒性（DLT）的发生无显著相关性。这可能是由于尼达尼布 PK 的个体内和个体间变异性较大。
尼达尼布剂量与 FVC 损失显著相关。然而，在这个真实世界的人群中，没有发现尼达尼布暴露与 DLT 发生之间存在显著关系，也无法确定治疗窗。本研究的结果表明，尼达尼布不适合进行 TDM。
