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首页> 外文期刊>The Journal of Clinical Pharmacology: Official Journal of the American College of Clinical Pharmacology >Pharmacokinetic Properties of Nintedanib in Healthy Volunteers and Patients With Advanced Cancer
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Pharmacokinetic Properties of Nintedanib in Healthy Volunteers and Patients With Advanced Cancer

机译：Nintedanib在健康志愿者和晚期癌症患者中的药代动力学特性

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Nintedanib, a triple angiokinase inhibitor, has undergone clinical investigation for the treatment of solid tumors and idiopathic pulmonary fibrosis. Nintedanib (Vargatef((R))) plus docetaxel is approved in the EU for the treatment of patients with adenocarcinoma non-small cell lung cancer (NSCLC) after first-line chemotherapy, and as monotherapy (Ofev((R))) in the United States and EU for the treatment of patients with idiopathic pulmonary fibrosis. Pharmacokinetics (PK) of nintedanib after oral single and multiple doses and intravenous (IV) administration were assessed using 3 data sets: (1) an absolute bioavailability trial that enrolled 30 healthy volunteers; (2) a pooled data analysis of 4 studies that enrolled a total of 107 healthy volunteers; and (3) a pooled data analysis of 4 studies that enrolled a total of 149 patients with advanced cancer. In the absolute bioavailability trial of healthy volunteers, nintedanib showed a high total clearance (geometric mean 1390 mL/min) and a high volume of distribution at steady state (V-ss=1050L). Urinary excretion of IV nintedanib was about 1% of dose; renal clearance was about 20mL/min and therefore negligible. There was no deviation from dose proportionality after IV administration in the dose range tested. Absolute bioavailability of oral nintedanib (100mg capsule) relative to IV dosing (4-hour infusion, 6mg) was slightly below 5%. Nintedanib was quickly absorbed after oral administration. It underwent rapid and extensive first-pass metabolism and followed at least biphasic disposition kinetics. In advanced cancer patients, steady state was reached at the latest at 7days for twice-daily dosing. Nintedanib's PK was time-independent; accumulation after repeated administration was negligible.
机译：Nintedanib，一种三联血管激酶抑制剂，已经过临床研究，用于治疗实体瘤和特发性肺纤维化。 Nintedanib（Vargatef（R））加上多西他赛已获欧盟批准用于一线化疗后的腺癌非小细胞肺癌（NSCLC）患者的治疗，并作为单药疗法（Ofev（R））美国和欧盟用于治疗特发性肺纤维化患者。口服单次和多次剂量以及静脉内（IV）给药后nintedanib的药代动力学（PK）使用以下3组数据进行评估：（1）一项绝对生物利用度试验，招募了30名健康志愿者。 （2）对4项研究的汇总数据分析，共纳入107名健康志愿者; （3）对4项研究的汇总数据分析，共纳入149名晚期癌症患者。在健康志愿者的绝对生物利用度试验中，nintedanib显示出较高的总清除率（几何平均值为1390 mL / min），并且在稳态下的分布体积较大（V-ss = 1050L）。静脉注射nintedanib的尿排泄量约为剂量的1％。肾脏清除率约为20mL / min，因此可以忽略不计。在所测试的剂量范围内，静脉内给药后与剂量比例没有偏差。相对于静脉给药（4小时输注，6mg），口服nintedanib（100mg胶囊）的绝对生物利用度略低于5％。 Nintedanib口服后迅速吸收。它经历了快速和广泛的首过代谢，并至少遵循了双相处置动力学。在晚期癌症患者中，最迟在第7天达到每日两次的稳定状态。 Nintedanib的PK与时间无关。重复给药后的积聚微不足道。

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