Medicine Design (M.E.D), Inflammation and Immunology (T.H.L., J.-B.T.), and Clinical Pharmacology (C.B.), Pfizer Inc., Cambridge, Massachusetts; Medicine Design (J.N.B., A.C.D., A.K.-A., R.S., G.S.W., J.L., T.C.G.) and Clinical Pharmacology (S.T.), Pfizer Inc., Groton, Connecticut; and Clinical Pharmacology, Pfizer Inc., New York, New York (B.K.M.).
Medicine Design (M.E.D), Inflammation and Immunology (T.H.L., J.-B.T.), and Clinical Pharmacology (C.B.), Pfizer Inc., Cambridge, Massachusetts; Medicine Design (J.N.B., A.C.D., A.K.-A., R.S., G.S.W., J.L., T.C.G.) and Clinical Pharmacology (S.T.), Pfizer Inc., Groton, Connecticut; and Clinical Pharmacology, Pfizer Inc., New York, New York (B.K.M.)
Drug Metab Dispos. 2022 Aug;50(8):1106-1118. doi: 10.1124/dmd.122.000829. Epub 2022 Jun 14.
Abrocitinib is an oral once-daily Janus kinase 1 selective inhibitor being developed for the treatment of moderate-to-severe atopic dermatitis. This study examined the disposition of abrocitinib in male participants following oral and intravenous administration using accelerator mass spectroscopy methodology to estimate pharmacokinetic parameters and characterize metabolite (M) profiles. The results indicated abrocitinib had a systemic clearance of 64.2 L/h, a steady-state volume of distribution of 100 L, extent of absorption >90%, time to maximum plasma concentration of ∼0.5 hours, and absolute oral bioavailability of 60%. The half-life of both abrocitinib and total radioactivity was similar, with no indication of metabolite accumulation. Abrocitinib was the main circulating drug species in plasma (∼26%), with 3 major monohydroxylated metabolites (M1, M2, and M4) at >10%. Oxidative metabolism was the primary route of elimination for abrocitinib, with the greatest disposition of radioactivity shown in the urine (∼85%). In vitro phenotyping indicated abrocitinib cytochrome P450 fraction of metabolism assignments of 0.53 for CYP2C19, 0.30 for CYP2C9, 0.11 for CYP3A4, and ∼0.06 for CYP2B6. The principal systemic metabolites M1, M2, and M4 were primarily cleared renally. Abrocitinib, M1, and M2 showed pharmacology with similar Janus kinase 1 selectivity, whereas M4 was inactive. SIGNIFICANCE STATEMENT: This study provides a detailed understanding of the disposition and metabolism of abrocitinib, a Janus kinase inhibitor for atopic dermatitis, in humans, as well as characterization of clearance pathways and pharmacokinetics of abrocitinib and its metabolites.
阿布昔替尼是一种每日口服一次的 Janus 激酶 1 选择性抑制剂，目前正在开发用于治疗中重度特应性皮炎。本研究采用加速质谱分析法评估药代动力学参数和表征代谢物（M）谱，考察了阿布昔替尼在男性参与者口服和静脉给药后的处置情况。结果表明，阿布昔替尼的全身清除率为 64.2 L/h，稳态分布容积为 100 L，吸收程度>90%，达最大血浆浓度时间约为 0.5 小时，绝对口服生物利用度为 60%。阿布昔替尼和总放射性的半衰期相似，无代谢物蓄积的迹象。阿布昔替尼是血浆中主要的循环药物种类（约 26%），有 3 种主要的单羟基化代谢物（M1、M2 和 M4）>10%。氧化代谢是阿布昔替尼的主要消除途径，放射性物质主要通过尿液排泄（约 85%）。体外表型分析表明，阿布昔替尼的细胞色素 P450 代谢分数为 CYP2C19 的 0.53、CYP2C9 的 0.30、CYP3A4 的 0.11 和 CYP2B6 的 ∼0.06。主要的全身性代谢物 M1、M2 和 M4 主要通过肾脏清除。阿布昔替尼、M1 和 M2 显示出与 Janus 激酶 1 相似的选择性，而 M4 无活性。 本研究提供了人类特应性皮炎 Janus 激酶抑制剂阿布昔替尼的处置和代谢的详细了解，以及对清除途径和阿布昔替尼及其代谢物的药代动力学的特征描述。
