Lathia Chetan, Lettieri John, Cihon Frank, Gallentine Martha, Radtke Martin, Sundaresan Pavur
Bayer Corporation, 400 Morgan Lane, West Haven, CT, 06516, USA.
Cancer Chemother Pharmacol. 2006 May;57(5):685-92. doi: 10.1007/s00280-005-0068-6. Epub 2005 Aug 25.
Sorafenib is a novel, small-molecule anticancer compound that inhibits tumor cell proliferation by targeting Raf in the Raf/MEK/ERK signalling pathway, and inhibits angiogenesis by targeting tyrosine kinases such as vascular-endothelial growth factor receptor (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor (PDGFR). In vitro microsomal data indicate that sorafenib is metabolized by two pathways: phase I oxidation mediated by cytochrome P450 (CYP) 3A4; and phase II conjugation mediated by UGT1A9. Approximately 50% of an orally administered dose is recovered as unchanged drug in the feces, due to either biliary excretion or lack of absorption. The aim of this study was to evaluate the effect of CYP3A inhibition by ketoconazole on sorafenib pharmacokinetics. This was an open-label, non-randomized, 2-period, one-way crossover study in sixteen healthy male subjects. A single 50 mg dose of sorafenib was administered alone (period 1) and in combination with ketoconazole 400 mg once daily (period 2) (ketoconazole was given for 7 days, and a single 50 mg sorafenib dose was administered concomitantly on day 4). No clinically relevant change in pharmacokinetics of sorafenib and no clinically relevant adverse events or laboratory abnormalities were observed in this study upon co-administration of the two drugs. Plasma concentrations of the main CYP3A4 generated metabolite, sorafenib N-oxide, decreased considerably upon ketoconazole co-administration. This effect is in accordance with the in vitro finding that CYP3A4 is the primary enzyme for sorafenib N-oxide formation. Further, these data indicate that blocking sorafenib metabolism by the CYP3A4 pathway will not lead to an increase in sorafenib exposure. This is consistent with data from a clinical mass-balance study that showed 15% of the administered dose was eliminated by glucuronidation, compared to less than 5% eliminated as oxidative metabolites. Since there was no increase in sorafenib exposure following concomitant administration of the highly potent CYP3A4 inhibitor ketoconazole with low dose sorafenib, it is postulated that higher therapeutic doses of sorafenib may be safely co-administered with ketoconazole, as well as with other inhibitors of CYP3A.
索拉非尼是一种新型小分子抗癌化合物，它通过作用于Raf/MEK/ERK信号通路中的Raf来抑制肿瘤细胞增殖，并通过作用于酪氨酸激酶（如血管内皮生长因子受体（VEGFR - 2和VEGFR - 3）以及血小板衍生生长因子受体（PDGFR））来抑制血管生成。体外微粒体数据表明，索拉非尼通过两条途径代谢：由细胞色素P450（CYP）3A4介导的I相氧化；以及由UGT1A9介导的II相结合。口服给药剂量中约50%以原形药物形式在粪便中回收，这是由于胆汁排泄或吸收不良所致。本研究的目的是评估酮康唑抑制CYP3A对索拉非尼药代动力学的影响。这是一项在16名健康男性受试者中进行的开放标签、非随机、两期、单向交叉研究。单次给予50mg索拉非尼（第1期），并与酮康唑400mg每日一次联合给药（第2期）（酮康唑给药7天，在第4天同时给予单次50mg索拉非尼剂量）。在本研究中，两种药物联合给药后未观察到索拉非尼药代动力学的临床相关变化，也未观察到临床相关不良事件或实验室异常。酮康唑联合给药后，主要的CYP3A4生成代谢产物索拉非尼N - 氧化物的血浆浓度显著降低。这一效应与体外研究结果一致，即CYP3A4是索拉非尼N - 氧化物形成的主要酶。此外，这些数据表明，通过CYP3A4途径阻断索拉非尼代谢不会导致索拉非尼暴露增加。这与一项临床质量平衡研究的数据一致，该研究表明，给药剂量的15%通过葡萄糖醛酸化消除，而作为氧化代谢产物消除的不到5%。由于在低剂量索拉非尼与强效CYP3A4抑制剂酮康唑联合给药后，索拉非尼暴露没有增加，因此推测更高治疗剂量的索拉非尼可能可以安全地与酮康唑以及其他CYP3A抑制剂联合使用。
