Genentech Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.
Covance Clinical Research Unit, 3402 Kinsman Boulevard, Madison, WI, 53704, USA.
Br J Clin Pharmacol. 2019 Aug;85(8):1751-1760. doi: 10.1111/bcp.13961. Epub 2019 Jun 14.
Navoximod (GDC-0919, NLG-919) is a small molecule inhibitor of indoleamine-2,3-dioxygenase 1 (IDO1), developed to treat the acquired immune tolerance associated with cancer. The primary objectives of this study were to assess navoximod's absolute bioavailability (aBA), determine the mass balance and routes of elimination of [ C]-navoximod, and characterize navoximod's metabolite profile.
A phase 1, open-label, two-part study was conducted in healthy volunteers. In Part 1 (aBA), subjects (n = 16) were randomized to receive oral (200 mg tablet) or intravenous (5 mg solution) navoximod in a crossover design with a 5-day washout. In Part 2 (mass balance), subjects (n = 8) were administered [ C]-navoximod (200 mg/600 μCi) as an oral solution.
The aBA of navoximod was estimated to be 55.5%, with a geometric mean (%CV) plasma clearance and volume of distribution of 62.0 L/h (21.0%) and 1120 L (28.4%), respectively. Mean recovery of total radioactivity was 87.8%, with 80.4% detected in urine and the remainder (7.4%) in faeces. Navoximod was extensively metabolized, with unchanged navoximod representing 5.45% of the dose recovered in the urine and faeces. Glucuronidation was identified as the primary route of metabolism, with the major glucuronide metabolite, M28, accounting for 57.5% of the total drug-derived exposure and 59.7% of the administered dose recovered in urine.
Navoximod was well tolerated, quickly absorbed and showed moderate bioavailability, with minimal recovery of the dose as unchanged parent in the urine and faeces. Metabolism was identified as the primary route of clearance and navoximod glucuronide (M28) was the most abundant metabolite in circulation with all other metabolites accounting for <10% of drug-related exposure.
纳武莫德（GDC-0919，NLG-919）是一种小分子 IDO1 抑制剂，用于治疗与癌症相关的获得性免疫耐受。本研究的主要目的是评估纳武莫德的绝对生物利用度（aBA），确定[C]-纳武莫德的物质平衡和消除途径，并表征纳武莫德的代谢产物谱。
一项在健康志愿者中进行的 1 期、开放标签、两部分研究。在第 1 部分（aBA）中，受试者（n=16）以交叉设计随机接受口服（200mg 片剂）或静脉内（5mg 溶液）纳武莫德给药，洗脱期为 5 天。在第 2 部分（物质平衡）中，受试者（n=8）口服给予[C]-纳武莫德（200mg/600μCi）溶液。
纳武莫德的 aBA 估计为 55.5%，其几何平均（%CV）血浆清除率和分布容积分别为 62.0L/h（21.0%）和 1120L（28.4%）。总放射性回收率的平均值为 87.8%，80.4%在尿液中检测到，其余（7.4%）在粪便中。纳武莫德被广泛代谢，未改变的纳武莫德占尿液和粪便中回收剂量的 5.45%。葡萄糖醛酸化被确定为主要代谢途径，主要的葡萄糖醛酸代谢物 M28 占总药物暴露的 57.5%和尿液中回收的给药剂量的 59.7%。
纳武莫德耐受性良好，吸收迅速，生物利用度中等，尿液和粪便中未改变的原型药物回收率低。代谢被确定为主要清除途径，纳武莫德葡萄糖醛酸（M28）是循环中最丰富的代谢物，其他所有代谢物的药物相关暴露均<10%。
