Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany.
Boehringer Ingelheim France S.A.S., Reims, France.
J Clin Pharmacol. 2018 Mar;58(3):357-363. doi: 10.1002/jcph.1025. Epub 2017 Nov 6.
Nintedanib is an intracellular inhibitor of tyrosine kinases used in the treatment of non-small cell lung cancer and idiopathic pulmonary fibrosis (IPF). This phase 1 open-label study investigated the influence of mild and moderate hepatic impairment on the pharmacokinetics (PK), safety, and tolerability of nintedanib following oral administration of a single 100-mg dose. Subjects with hepatic impairment classified as Child-Pugh A (mild hepatic impairment) or Child-Pugh B (moderate hepatic impairment) were eligible. The control group comprised healthy matched subjects. Primary end points were C and AUC of nintedanib. Thirty-three subjects received nintedanib (8 in each of the Child-Pugh A and Child-Pugh B groups and 17 controls). The shape of the plasma concentration-time curve for nintedanib was similar between Child-Pugh A or B and healthy subjects. Nintedanib exposure was ∼2-fold higher in Child-Pugh A subjects and ∼8-fold higher in Child-Pugh B subjects than in healthy subjects. Adverse events were reported in 3 Child-Pugh B subjects (37.5%), no Child-Pugh A subjects, and 3 healthy subjects (17.6%). In conclusion, exposure to nintedanib was higher in Child-Pugh A and B subjects than in matched healthy subjects. A single dose of nintedanib 100 mg had an acceptable safety and tolerability profile in subjects with hepatic impairment. Results of this dedicated phase 1 study are in line with exploratory investigations into the PK of nintedanib in patients with advanced solid tumors or IPF and hepatic impairment.
尼达尼布是一种细胞内酪氨酸激酶抑制剂，用于治疗非小细胞肺癌和特发性肺纤维化（IPF）。这项 1 期开放标签研究调查了轻度和中度肝损伤对单剂 100mg 口服尼达尼布后药代动力学（PK）、安全性和耐受性的影响。肝损伤分类为 Child-Pugh A（轻度肝损伤）或 Child-Pugh B（中度肝损伤）的患者有资格参加。对照组由健康匹配的受试者组成。主要终点是尼达尼布的 C 和 AUC。33 名受试者接受了尼达尼布（Child-Pugh A 或 B 组各 8 名，对照组 17 名）。尼达尼布的血浆浓度-时间曲线形状在 Child-Pugh A 或 B 与健康受试者之间相似。Child-Pugh A 受试者的尼达尼布暴露量约为健康受试者的 2 倍，Child-Pugh B 受试者的尼达尼布暴露量约为健康受试者的 8 倍。Child-Pugh B 组的 3 名受试者（37.5%）、Child-Pugh A 组无受试者和 3 名健康受试者（17.6%）报告了不良事件。结论：Child-Pugh A 和 B 受试者的尼达尼布暴露量高于匹配的健康受试者。尼达尼布 100mg 单剂量在肝损伤受试者中具有可接受的安全性和耐受性。这项专门的 1 期研究的结果与尼达尼布在晚期实体瘤或 IPF 和肝损伤患者中的 PK 的探索性研究一致。
