GSK, Collegeville, Pennsylvania (B.W., Y.Z., J.P., J.D., J.Z.); GSK, Ware, United Kingdom (G.C.Y., D.K.); GSK, Stevenage, United Kingdom (A.P., B.J.); and ViiV Healthcare, Durham, North Carolina (M.J.)
GSK, Collegeville, Pennsylvania (B.W., Y.Z., J.P., J.D., J.Z.); GSK, Ware, United Kingdom (G.C.Y., D.K.); GSK, Stevenage, United Kingdom (A.P., B.J.); and ViiV Healthcare, Durham, North Carolina (M.J.).
Drug Metab Dispos. 2022 Nov;50(11):1442-1453. doi: 10.1124/dmd.122.000955. Epub 2022 Sep 24.
GSK3640254 is a next-generation maturation inhibitor in development for HIV-1 treatment, with pharmacokinetics (PK) supporting once-daily oral dosing in human. This open-label, nonrandomized, two-period clinical mass balance and excretion study was used to investigate the excretion balance, PK, and metabolism of GSK3640254. Five healthy men received a single intravenous microtracer of 100 g [C]GSK3640254 with a concomitant oral nonradiolabeled 200-mg tablet followed by an oral 85-mg dose of [C]GSK3640254 14 days later. Complementary methods, including intravenous microtracing and accelerator mass spectrometry, allowed characterization of several parameters, including fraction absorbed, fraction escaping gut metabolism, hepatic extraction ratio, and renal clearance. Intravenous PK of GSK3640254 was characterized by low plasma clearance (1.04 l/h), moderate terminal phase half-life (21.7 hours), and low volume of distribution at steady state (28.7 L). Orally dosed GSK3640254 was absorbed (fraction absorbed, 0.26), with a high fraction escaping gut metabolism (0.898) and a low hepatic extraction ratio (0.00544), all consistent with low in vitro intrinsic clearance in liver microsomes and hepatocytes. No major metabolites in human plasma required further qualification in animal studies. Both unchanged parent GSK3640254 and its oxidative and conjugative metabolites were excreted into bile, with GSK3640254 likely subject to further metabolism through enterohepatic recirculation. Renal elimination of GSK3640254 as the parent drug or its metabolites was negligible, with >94% of total recovery of oral dose and >99% of the recovered radioactivity in feces. Altogether, the data suggest that systemically available GSK3640254 was slowly eliminated almost entirely by hepatobiliary secretion, primarily as conjugative and oxidative metabolites. SIGNIFICANCE STATEMENT: The combination of an intravenous C microtracer with duodenal bile sampling using EnteroTracker in a human absorption, distribution, metabolism, and excretion study enabled derivation of absorption and first-pass parameters, including fraction absorbed, proportion escaping first-pass extraction through the gut wall and liver, hepatic extraction, and other conventional clinical pharmacokinetic parameters. This approach identified hepatic metabolism and biliary excretion as a major elimination pathway for absorbed drug, which would be overlooked based solely on analyses of plasma, urine, and fecal matrices.
GSK3640254 是一种用于治疗 HIV-1 的下一代成熟抑制剂，其药代动力学（PK）支持人类每天口服一次。这项开放标签、非随机、两期临床物质平衡和排泄研究用于研究 GSK3640254 的排泄平衡、PK 和代谢。五名健康男性接受了单次静脉微量示踪剂 100 g [C]GSK3640254，并同时口服 200mg 非放射性片剂，14 天后口服 85mg [C]GSK3640254。补充方法，包括静脉微量示踪和加速器质谱法，允许对多个参数进行特征描述，包括吸收分数、肠道代谢逃逸分数、肝提取比和肾清除率。GSK3640254 的静脉 PK 特征为低血浆清除率（1.04 l/h）、中等终末半衰期（21.7 小时）和稳态下低分布容积（28.7 L）。口服给予 GSK3640254 被吸收（吸收分数为 0.26），肠道代谢逃逸分数高（0.898），肝提取比低（0.00544），这与肝微粒体和肝细胞中低内在清除率一致。在动物研究中无需进一步鉴定人血浆中的主要代谢物。未改变的母体 GSK3640254 及其氧化和结合代谢物均被排泄到胆汁中，GSK3640254 可能通过肠肝再循环进一步代谢。GSK3640254 作为母体药物或其代谢物的肾脏消除可忽略不计，口服剂量的总回收率超过 94%，粪便中回收的放射性超过 99%。总的来说，数据表明，系统可利用的 GSK3640254 几乎完全通过肝胆分泌缓慢消除，主要作为结合和氧化代谢物。意义：在一项人类吸收、分布、代谢和排泄研究中，将静脉 C 微示踪剂与使用 EnteroTracker 的十二指肠胆汁采样相结合，使吸收和首次通过参数得以推导，包括吸收分数、通过肠壁和肝脏首次通过提取逃逸的比例、肝提取率和其他常规临床药代动力学参数。这种方法确定了肝代谢和胆汁排泄是吸收药物的主要消除途径，如果仅基于对血浆、尿液和粪便基质的分析，这将被忽视。
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