Effects of Itraconazole and Diltiazem on the Pharmacokinetics and Pharmacodynamics of Milvexian, A Factor XIa Inhibitor

Vidya Perera; Zhaoqing Wang; Susan Lubin; Lisa J Christopher; Wei Chen; Sophia Xu; Dietmar Seiffert; Mary DeSouza; Bindu Murthy

doi:10.1007/s40119-022-00266-6

Effects of Itraconazole and Diltiazem on the Pharmacokinetics and Pharmacodynamics of Milvexian, A Factor XIa Inhibitor

Cardiol Ther. 2022 Sep;11(3):407-419. doi: 10.1007/s40119-022-00266-6. Epub 2022 May 31.

Authors

Vidya Perera¹, Zhaoqing Wang², Susan Lubin², Lisa J Christopher², Wei Chen², Sophia Xu², Dietmar Seiffert², Mary DeSouza², Bindu Murthy²

Affiliations

¹ Bristol Myers Squibb, 3401 Princeton Pike, Lawrenceville, NJ, 08648, USA. vidya.perera@bms.com.
² Bristol Myers Squibb, 3401 Princeton Pike, Lawrenceville, NJ, 08648, USA.

Abstract

Introduction: 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.

Methods: 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.

Results: A total of 28 participants entered the treatment period. Following itraconazole co-administration, milvexian exposure was increased; AUC_(0-T), AUC_(INF), and C₂₄ were 2.5-, 2.5-, and 3.8-fold higher, while mean C_max was 28% higher versus milvexian alone. Diltiazem co-administration also increased milvexian exposure; AUC_(0-T), AUC_(INF), and C₂₄ were 38, 38, and 64% higher, and mean C_max 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.

Conclusions: 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.

Trial registration: The study was registered with ClinicalTrials.gov (NCT02807909; submitted June 17, 2016).

Keywords: Anticoagulation; Drug–drug interactions; Factor XIa inhibition; Pharmacodynamics; Pharmacokinetics.

Associated data

ClinicalTrials.gov/NCT02807909