Perera Vidya, Wang Zhaoqing, Lubin Susan, Christopher Lisa J, Chen Wei, Xu Sophia, Seiffert Dietmar, DeSouza Mary, Murthy Bindu
Bristol Myers Squibb, 3401 Princeton Pike, Lawrenceville, NJ, 08648, USA.
Cardiol Ther. 2022 Sep;11(3):407-419. doi: 10.1007/s40119-022-00266-6. Epub 2022 May 31.
Modulation of Factor XIa (FXIa) may provide a novel mechanism for systemic anticoagulation with the potential to improve the risk-benefit profile observed with existing anticoagulants through greater efficacy or a safer bleeding profile. This study assessed the effects of co-administration with strong and moderate CYP3A inhibitors itraconazole and diltiazem, respectively, on the pharmacokinetic and pharmacodynamic properties of milvexian, a Factor XIa inhibitor.
This was an open-label, non-randomized, two-period crossover study in healthy participants. In period 1, participants received a single oral dose of milvexian (30 mg) on day 1, followed by a washout on days 2 and 3. In period 2, participants received multiple oral doses of itraconazole (200 mg) or diltiazem (240 mg) with a single dose of milvexian.
A total of 28 participants entered the treatment period. Following itraconazole co-administration, milvexian exposure was increased; AUC, AUC, and C were 2.5-, 2.5-, and 3.8-fold higher, while mean C was 28% higher versus milvexian alone. Diltiazem co-administration also increased milvexian exposure; AUC, AUC, and C were 38, 38, and 64% higher, and mean C was 9.6% higher versus milvexian alone. Prolongation of activated partial thromboplastin time was observed with milvexian in a concentration-dependent fashion irrespective of co-administration with itraconazole or diltiazem. Administration of a single dose of milvexian, alone or in combination with itraconazole or diltiazem, was generally safe and well tolerated; there were no deaths or serious adverse events.
A moderate increase in milvexian exposure was observed following co-administration of itraconazole while a minimal increase was seen with diltiazem, consistent with the involvement of CYP3A metabolism and P-glycoprotein in drug absorption/elimination. Milvexian was generally safe and well tolerated in healthy participants.
The study was registered with ClinicalTrials.gov (NCT02807909; submitted June 17, 2016).
因子 XIa（FXIa）的调节可能为全身抗凝提供一种新机制，有望通过更高的疗效或更安全的出血情况来改善现有抗凝剂的风险效益比。本研究分别评估了与强效和中效 CYP3A 抑制剂伊曲康唑和地尔硫䓬联合用药对 FXIa 抑制剂米尔维先的药代动力学和药效学特性的影响。
这是一项针对健康参与者的开放标签、非随机、两期交叉研究。在第 1 期，参与者于第 1 天口服单剂量米尔维先（30 毫克），随后在第 2 天和第 3 天进行洗脱期。在第 2 期，参与者接受多剂量伊曲康唑（200 毫克）或地尔硫䓬（240 毫克）与单剂量米尔维先联合用药。
共有 28 名参与者进入治疗期。与伊曲康唑联合用药后，米尔维先的暴露量增加；AUC、AUC 和 C 分别高出 2.5 倍、2.5 倍和 3.8 倍，而平均 C 比单独使用米尔维先时高出 28%。与地尔硫䓬联合用药也增加了米尔维先的暴露量；AUC、AUC 和 C 分别高出 38%、38%和 64%，平均 C 比单独使用米尔维先时高出 9.6%。无论是否与伊曲康唑或地尔硫䓬联合用药，米尔维先均以浓度依赖方式延长活化部分凝血活酶时间。单独或与伊曲康唑或地尔硫䓬联合使用单剂量米尔维先总体上是安全的且耐受性良好；未发生死亡或严重不良事件。
与伊曲康唑联合用药后观察到米尔维先暴露量适度增加，与地尔硫䓬联合用药时增加幅度最小，这与 CYP3A 代谢和 P-糖蛋白参与药物吸收/消除一致。米尔维先在健康参与者中总体上是安全的且耐受性良好。
该研究已在 ClinicalTrials.gov 注册（NCT02807909；2016 年 6 月 17 日提交）。
