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首页> 外文期刊>The Journal of Clinical Pharmacology: Official Journal of the American College of Clinical Pharmacology >In Vivo Assessment of the Effect of CYP1A2 Inhibition and Induction on Pomalidomide Pharmacokinetics in Healthy Subjects
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In Vivo Assessment of the Effect of CYP1A2 Inhibition and Induction on Pomalidomide Pharmacokinetics in Healthy Subjects

机译：体内评估CYP1A2抑制和诱导对健康受试者茂米多德药代动力学的影响

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Abstract Pomalidomide is an immunomodulatory drug, and the dosage of 4 mg per day taken orally on days 1‐21 of repeated 28‐day cycles has been approved in the European Union and the United States to treat patients with relapsed/refractory multiple myeloma. In vitro data showed that pomalidomide is a substrate of multiple cytochrome P450 (CYP) isozymes and that its oxidative metabolism is mediated primarily by CYP1A2 and CYP3A4, with minor contributions from CYP2C19 and CYP2D6. The effect of CYP1A2 inhibition by fluvoxamine (a strong CYP1A2 inhibitor) and CYP1A2 induction by smoking on pomalidomide pharmacokinetics in healthy subjects has been assessed in 2 separate phase 1 open‐label, single‐dose studies. Following administration of a single oral dose of 4 mg pomalidomide, the plasma exposure when coadministered with fluvoxamine was 225.1% and 123.7% of that when administered alone for the total plasma exposure (AUC 0‐inf ) and the plasma peak exposure (C max ), respectively. In smokers with elevated CYP1A2 activity demonstrated by high caffeine clearance (a marker of CYP1A2 induction), the AUC 0‐inf was 32.3% lower, whereas the C max was 14.4% higher than that in nonsmokers. In addition, pomalidomide was safe and well tolerated as a single oral dose of 4 mg in healthy male smokers and nonsmokers ≥ 40 to ≤ 80 years old, and a single oral dose of 4 mg pomalidomide coadministered with multiple oral 50‐mg doses of the CYP1A2 inhibitor fluvoxamine compared with pomalidomide alone was safe and well tolerated by the healthy male subjects.
机译：摘要氟三胺是一种免疫调节药物，在欧盟和美国在重复的28天循环中口服每天4毫克/天的剂量已被批准，以治疗复发/难治性多发性骨髓瘤的患者。体外数据显示，氯烃是多种细胞色素P450（CYP）同工酶的底物，其氧化代谢主要由CYP1A2和CYP3A4介导，来自CYP2C19和CYP2D6的轻微贡献。通过在2个单独的第1期开放标记，单剂量研究中评估了氟诺莫胺（强CYP1A2抑制剂）和CYP1A2诱导对健康受试者的茂密醛药代动力学进行诱导的影响。在施用单个口服剂量4mg氟三胺后，当单独给予总血浆暴露（AUC 0-INF）和等离子体峰值暴露（C MAX）时，在氟诺莫胺共同施用时，血浆曝光率为225.1％和123.7％。 ， 分别。在具有高咖啡因清除（CYP1A2诱导的CYP1A2诱导标记的CYP1A2活性的吸烟者中，AUC 0-INF的较低32.3％，而C MAX比非莫克者高出14.4％。此外，氟三胺在健康男性吸烟者中为4毫克的单个口服剂量和≥40至80岁的单一口服剂量安全且耐受良好的耐受性，并且单一口服剂量为4毫克·氯溴代胺，具有多种口腔50mg剂量的剂量CYP1A2抑制剂氟戊胺与单独的氟三元胺相比，通过健康的男性受试者安全且良好耐受。

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