Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb Company, Princeton, New Jersey, USA.
J Clin Pharmacol. 2012 Jun;52(6):914-21. doi: 10.1177/0091270011407495. Epub 2011 Jun 9.
Brivanib alaninate is the orally available prodrug of brivanib, a dual inhibitor of fibroblast growth factor and vascular endothelial growth factor signaling pathways that is under therapeutic investigation for various malignancies. Brivanib alaninate inhibits CYP3A4 in vitro, and thus there is potential for drug-drug interaction with CYP3A4 substrates, such as midazolam. The present study evaluated pharmacokinetic parameters and safety/tolerability upon coadministration of brivanib alaninate and midazolam. Healthy participants received intravenous (IV) or oral midazolam with and without oral brivanib alaninate. Blood samples for pharmacokinetic analysis were collected up to 12 hours after midazolam and up to 48 hours after brivanib alaninate. Twenty-four participants were administered study drugs; 21 completed the trial. No clinically relevant effect of brivanib alaninate on the overall exposure to midazolam following IV or oral administration was observed. Orally administered brivanib alaninate was generally well tolerated in the presence of IV or oral midazolam. The lack of a pharmacokinetic interaction between brivanib and midazolam indicates that brivanib alaninate does not influence either intestinal or hepatic CYP3A4 and confirms that brivanib alaninate may be safely coadministered with midazolam and other CYP3A4 substrates.
布立尼布丙氨酸是布立尼布的口服前体药物，布立尼布是一种成纤维细胞生长因子和血管内皮生长因子信号通路的双重抑制剂，正在各种恶性肿瘤的治疗中进行研究。布立尼布丙氨酸在体外抑制 CYP3A4，因此与 CYP3A4 底物（如咪达唑仑）存在药物相互作用的潜力。本研究评估了布立尼布丙氨酸和咪达唑仑联合给药时的药代动力学参数和安全性/耐受性。健康参与者接受静脉（IV）或口服咪达唑仑，同时给予或不给予口服布立尼布丙氨酸。在咪达唑仑给药后 12 小时内和布立尼布丙氨酸给药后 48 小时内采集用于药代动力学分析的血样。24 名参与者接受了研究药物；21 名完成了试验。静脉或口服给予咪达唑仑后，布立尼布丙氨酸对其总体暴露量无临床相关影响。在静脉或口服咪达唑仑存在的情况下，口服给予的布立尼布丙氨酸通常具有良好的耐受性。布立尼布和咪达唑仑之间不存在药代动力学相互作用表明，布立尼布丙氨酸既不影响肠道也不影响肝脏 CYP3A4，并证实布立尼布丙氨酸可与咪达唑仑和其他 CYP3A4 底物安全联合给药。
