Janssen Research & Development, Beerse, Belgium (R.d.V., F.J., G.M., J.S., F.C.); Janssen Research & Development, Spring House, Pennsylvania (C.C.); and Janssen Research & Development, San Diego, California (P.W.)
Janssen Research & Development, Beerse, Belgium (R.d.V., F.J., G.M., J.S., F.C.); Janssen Research & Development, Spring House, Pennsylvania (C.C.); and Janssen Research & Development, San Diego, California (P.W.).
Drug Metab Dispos. 2019 May;47(5):453-464. doi: 10.1124/dmd.118.084517. Epub 2019 Feb 20.
In this phase 1 study, the absolute bioavailability and absorption, metabolism, and excretion (AME) of apalutamide, a competitive inhibitor of the androgen receptor, were evaluated in 12 healthy men. Subjects received 240 mg of apalutamide orally plus a 15-minute intravenous infusion of 100 g of apalutamide containing 9.25 kBq (250 nCi) of C-apalutamide (2 hours postdose) for absolute bioavailability assessment or plus one 400-g capsule containing 37 kBq (1000 nCi) of C-apalutamide for AME assessment. Content of C and metabolite profiling for whole blood, plasma, urine, feces, and expired air samples were analyzed using accelerator mass spectrometry. Apalutamide absolute oral bioavailability was ≈100%. After oral administration, apalutamide, its -desmethyl metabolite (M3), and an inactive carboxylic acid metabolite (M4) accounted for most C in plasma (45%, 44%, and 3%, respectively). Apalutamide elimination was slow, with a mean plasma half-life of 151-178 hours. The mean cumulative recovery of total C over 70 days postdose was 64.6% in urine and 24.3% in feces. The urinary excretion of apalutamide, M3, and M4 was 1.2%, 2.7%, and 31.1% of dose, respectively. Fecal excretion of apalutamide, M3, and M4 was 1.5%, 2.0%, and 2.4% of dose, respectively. Seventeen apalutamide metabolites and six main metabolic clearance pathways were identified. In vitro studies confirmed CYP2C8 and CYP3A4 roles in apalutamide metabolism.
在这项 1 期研究中，评估了雄激素受体竞争性抑制剂阿帕鲁胺在 12 位健康男性中的绝对生物利用度和吸收、代谢和排泄（AME）。受试者口服 240mg 阿帕鲁胺，并在给药后 2 小时静脉输注 15 分钟含有 100μg 阿帕鲁胺（9.25kBq [250nCi]）的 100g 阿帕鲁胺溶液，用于绝对生物利用度评估，或口服 400mg 胶囊，其中含有 37kBq（1000nCi）的 C-阿帕鲁胺，用于 AME 评估。使用加速器质谱法分析全血、血浆、尿液、粪便和呼出空气样本中的 C 和代谢产物谱。阿帕鲁胺的口服绝对生物利用度约为 100%。口服后，阿帕鲁胺、其 -去甲基代谢物（M3）和无活性的羧酸代谢物（M4）在血浆中占 C 的大部分（分别为 45%、44%和 3%）。阿帕鲁胺消除缓慢，平均血浆半衰期为 151-178 小时。给药后 70 天内，总 C 的累计回收率在尿液中为 64.6%，在粪便中为 24.3%。阿帕鲁胺、M3 和 M4 的尿排泄量分别为剂量的 1.2%、2.7%和 31.1%。阿帕鲁胺、M3 和 M4 的粪便排泄量分别为剂量的 1.5%、2.0%和 2.4%。鉴定了 17 种阿帕鲁胺代谢物和 6 种主要代谢清除途径。体外研究证实了 CYP2C8 和 CYP3A4 在阿帕鲁胺代谢中的作用。
