吉非替尼与利福平、伊曲康唑和美托洛尔的药代动力学相互作用。

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斯瓦伊兰HC，兰森M，史密斯RP，利百特J，莱特A，麦克基洛普D，怀尔德MJ

吉非替尼与利福平、伊曲康唑和美托洛尔的药代动力学相互作用。

临床药典杂志2005;44(10):1067-81。doi: 10.2165 / 00003088-200544100-00005。

PubMed ID

16176119 (PubMed视图

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摘要

背景和目的:吉非替尼(Gefitinib, IRESSA, ZD1839)是一种表皮生长因子受体酪氨酸激酶抑制剂，已被多个国家批准用于治疗晚期非小细胞肺癌。进行了临床前研究，以确定参与吉非替尼代谢的细胞色素P450 (CYP)同工酶，并评估吉非替尼通过抑制CYP同工酶引起药物相互作用的潜力。基于这些发现，开展了三项临床研究，以研究吉非替尼在体内的药代动力学药物相互作用。方法:在临床前研究中，放射性标记的吉非替尼与:(i)选择性CYP抑制剂存在下的肝微粒体蛋白孵育;(ii)表达CYP酶。人肝微粒体蛋白与选择性CYP底物在吉非替尼存在下孵育。临床研究均为I期、开放标签、单中心研究;其中两个是随机的双向交叉设计，第三个是非随机的。第一项和第二项研究调查了在健康男性志愿者中存在有效CYP3A4诱导剂(利福平[利福平])或抑制剂(伊曲康唑)时吉非替尼的药代动力学。第三项研究调查了吉非替尼对实体肿瘤患者中CYP2D6底物美托洛尔药代动力学的影响。 RESULTS: The results of preclinical studies demonstrated that CYP3A4 is involved in the metabolism of gefitinib and that gefitinib is a weak inhibitor of CYP2D6 activity. In clinical studies when gefitinib was administered in the presence of rifampicin, geometric mean (gmean) maximum concentration and area under the plasma concentration-time curve (AUC) were reduced by 65% and 83%, respectively; these changes were statistically significant. When gefitinib was administered in the presence of itraconazole, gmean AUC increased by 78% and 61% at gefitinib doses of 250 and 500 mg, respectively; these changes also being statistically significant. Coadministration of metoprolol with gefitinib resulted in a 35% increase in the metoprolol area under plasma concentration-time curve from time zero to the time of the last quantifiable concentration; this change was not statistically significant. There was no apparent change in the safety profile of gefitinib as a result of coadministration with other agents. CONCLUSIONS: Although CYP3A4 inducers may reduce exposure to gefitinib, further work is required to define any resultant effect on the efficacy of gefitinib. Exposure to gefitinib is increased by coadministration with CYP3A4 inhibitors, but since gefitinib is known to have a good tolerability profile, a dosage reduction is not recommended. Gefitinib is unlikely to exert a clinically relevant effect on the pharmacokinetics of drugs that are dependent on CYP2D6-mediated metabolism for their clearance, but the potential to increase plasma concentrations should be considered if gefitinib is coadministered with CYP2D6 substrates that have a narrow therapeutic index or are individually dose titrated.

引用本文的药物库数据

药物酶

药物	酶	种类	生物	药理作用	行动
吉非替尼	细胞色素P450 2D6	蛋白质	人类	没有	底物 抑制剂	细节