一项I期、单中心、开放标签研究,旨在研究单次口服剂量100 mg[14 C]安可非尼用于健康男性受试者。

IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY
Lance Wollenberg, Erik Hahn, Jason Williams, Kevin Litwiler
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引用次数: 0

摘要

安可拉芬尼是BRAF V600E以及野生型BRAF和CRAF的新型激酶抑制剂,并已获得批准与二甲替尼联合治疗BRAF V600 E或V600 K突变阳性的不可切除或转移性黑色素瘤,或与西妥昔单抗联合治疗BRAF-V600 E突变阳性的癌症。通过给药[14C]encorafenib(100 mg含90 μCi)给4名健康男性受试者(NCT01436656)。对健康男性受试者单次口服100 mg剂量[14 C]安可非尼后,四名受试者排泄物中放射性的总体回收率均≥93.9%,表明达到了良好的质量平衡。粪便和尿液中放射性剂量的平均值为47.2%。在粪便(5.0%)和尿液(1.8%)中消除的剂量百分比为未改变的安可芬尼,是很小的。代谢被发现是安可芬尼在人体内的主要清除途径(约为回收放射性剂量的88%),主要通过异丙基氨基甲酸甲酯的N-脱烷基作用介导,形成初级1相直接代谢产物M42.5(LHY746)。根据尿液中回收的放射性剂量(47.2%)和粪便中回收的代谢产物总放射性剂量(39%)估计口服吸收。基于这些值以及安克拉芬尼及其代谢物在粪便中稳定的假设,估计口服吸收率至少为~86%。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

A phase I, single-center, open-label study to investigate the absorption, distribution, metabolism and excretion of encorafenib following a single oral dose of 100 mg [<sup>14</sup> C] encorafenib in healthy male subjects.

A phase I, single-center, open-label study to investigate the absorption, distribution, metabolism and excretion of encorafenib following a single oral dose of 100 mg [14 C] encorafenib in healthy male subjects.

Encorafenib is a novel kinase inhibitor of BRAF V600E as well as wild-type BRAF and CRAF and has received approval, in combination with binimetinib, to treat BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma or in combination with cetuximab to treat BRAF V600E mutation-positive colorectal cancer. The absorption, distribution, metabolism and excretion (ADME) of encorafenib was studied by administering [14 C] encorafenib (100 mg containing 90 μCi of radiolabeled material) to 4 healthy male subjects (NCT01436656). Following a single oral 100-mg dose of [14 C] encorafenib to healthy male subjects, the overall recovery of radioactivity in the excreta was ≥93.9% in all four subjects, indicating that good mass balance was achieved. An equal mean of 47.2% for the radioactivity dose was eliminated in the feces and urine. The percentage of the dose eliminated in the feces (5.0%) and urine (1.8%) as unchanged encorafenib was minor. Metabolism was found to be the major clearance pathway (~88% of the recovered radioactive dose) for encorafenib in humans and is predominantly mediated through N-dealkylation of the isopropyl carbamic acid methyl ester to form the primary phase 1 direct metabolite M42.5 (LHY746). Oral absorption was estimated from the radioactive dose recovered in the urine (47.2%) and the total radioactive dose recovered in the feces as metabolites (39%). Based on these values and the assumptions that encorafenib and its metabolites are stable in feces, the fraction of oral absorption was estimated to be at least ~86%.

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来源期刊
Pharmacology Research & Perspectives
Pharmacology Research & Perspectives Pharmacology, Toxicology and Pharmaceutics-General Pharmacology, Toxicology and Pharmaceutics
CiteScore
5.30
自引率
3.80%
发文量
120
审稿时长
20 weeks
期刊介绍: PR&P is jointly published by the American Society for Pharmacology and Experimental Therapeutics (ASPET), the British Pharmacological Society (BPS), and Wiley. PR&P is a bi-monthly open access journal that publishes a range of article types, including: target validation (preclinical papers that show a hypothesis is incorrect or papers on drugs that have failed in early clinical development); drug discovery reviews (strategy, hypotheses, and data resulting in a successful therapeutic drug); frontiers in translational medicine (drug and target validation for an unmet therapeutic need); pharmacological hypotheses (reviews that are oriented to inform a novel hypothesis); and replication studies (work that refutes key findings [failed replication] and work that validates key findings). PR&P publishes papers submitted directly to the journal and those referred from the journals of ASPET and the BPS
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