Drug Metabolism and Pharmacokinetics (R.H.T., B.M.L., S.C., Y.D., B.D., S.M.), Clinical Pharmacology (V.M., R.S., S.K., L.M.), BioAnalytical Sciences (J.N.), Small Molecule Pharmaceutics (E.Y.), and Small Molecule Analytical Chemistry (M.A.A.-S.), Genentech Inc., South San Francisco, California.
Drug Metabolism and Pharmacokinetics (R.H.T., B.M.L., S.C., Y.D., B.D., S.M.), Clinical Pharmacology (V.M., R.S., S.K., L.M.), BioAnalytical Sciences (J.N.), Small Molecule Pharmaceutics (E.Y.), and Small Molecule Analytical Chemistry (M.A.A.-S.), Genentech Inc., South San Francisco, California
Drug Metab Dispos. 2023 Oct;51(10):1332-1341. doi: 10.1124/dmd.122.001175. Epub 2023 Jul 31.
Ipatasertib (GDC-0068) is a potent, highly selective, small-molecule inhibitor of protein kinase B (Akt) being developed by Genentech/Roche as a single agent and in combination with other therapies for the treatment of cancers. To fully understand the absorption, metabolism, and excretion of ipatasertib in humans, an open-label study using C-radiolabeled ipatasertib was completed to characterize the absolute bioavailability (period 1) and mass balance and metabolite profiling (period 2). In period 1, subjects were administered a 200 mg oral dose of ipatasertib followed by an 80 g (800 nCi) intravenous dose of [C]-ipatasertib. In period 2, subjects received a single oral dose containing approximately 200 mg (100 Ci) [C]-ipatasertib. In an integrated analytical strategy, accelerator mass spectrometry was applied to measure the C microtracer intravenous pharmacokinetics in period 1 and fully profile plasma radioactivity in period 2. The systemic plasma clearance and steady-state volume of distribution were 98.8 L/h and 2530 L, respectively. The terminal half-lives after oral and intravenous administrations were similar (26.7 and 27.4 hours, respectively) and absolute bioavailability of ipatasertib was 34.0%. After a single oral dose of [C]-ipatasertib, 88.3% of the administered radioactivity was recovered with approximately 69.0% and 19.3% in feces and urine, respectively. Radioactivity in feces and urine was predominantly metabolites with 24.4% and 8.26% of dose as unchanged parent, respectively; indicating that ipatasertib had been extensively absorbed and hepatic metabolism was the major route of clearance. The major metabolic pathway was -dealkylation mediated by CYP3A, and minor pathways were oxidative by cytochromes P450 and aldehyde oxidase. SIGNIFICANCE STATEMENT: The study provided definitive information regarding the absolute bioavailability and the absorption, metabolism, and excretion pathways of ipatasertib, a potent, novel, and highly selective small-molecule inhibitor of protein kinase B (Akt). An ultrasensitive radioactive counting method, accelerator mass spectrometry was successfully applied for C-microtracer absolute bioavailability determination and plasma metabolite profiling.
伊帕替膦（GDC-0068）是一种有效的、高度选择性的小分子蛋白激酶 B（Akt）抑制剂，由基因泰克/罗氏开发，作为单一药物以及与其他疗法联合用于癌症治疗。为了全面了解伊帕替膦在人体内的吸收、代谢和排泄情况，完成了一项使用 C 放射性标记伊帕替膦的开放标签研究，以描述绝对生物利用度（第 1 期）和质量平衡及代谢产物分析（第 2 期）。第 1 期，受试者给予 200mg 口服伊帕替膦后，静脉给予 80g（800nCi）[C]-伊帕替膦。第 2 期，受试者给予单剂量约 200mg（100Ci）[C]-伊帕替膦。在综合分析策略中，应用加速器质谱法测量第 1 期 C 微示踪剂的静脉药代动力学，并在第 2 期全面分析血浆放射性。口服和静脉给药后的系统血浆清除率和稳态分布容积分别为 98.8L/h 和 2530L。口服和静脉给药后的终末半衰期相似（分别为 26.7 和 27.4 小时），伊帕替膦的绝对生物利用度为 34.0%。给予单剂量[C]-伊帕替膦后，88.3%的给予放射性物质从粪便和尿液中分别以 69.0%和 19.3%的比例回收。粪便和尿液中的放射性物质主要为代谢物，分别有 24.4%和 8.26%的剂量为未改变的母体；表明伊帕替膦已被广泛吸收，肝脏代谢是主要的清除途径。主要代谢途径是由 CYP3A 介导的去烷基化，次要途径是细胞色素 P450 和醛氧化酶的氧化。意义：该研究提供了关于伊帕替膦的绝对生物利用度以及吸收、代谢和排泄途径的明确信息，伊帕替膦是一种有效的新型高度选择性蛋白激酶 B（Akt）小分子抑制剂。一种超灵敏放射性计数方法，加速器质谱法成功地应用于 C 微示踪剂的绝对生物利用度测定和血浆代谢产物分析。
