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

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 C 24 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 C 24 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). Supplementary Information The online version contains supplementary material available at 10.1007/s40119-022-00266-6.

Pharmacology and Clinical Development of Factor XI Inhibitors

“…Of note, small molecules depend on the liver for their metabolism, and significant interactions with cytochrome P450 3A4 have been observed so far only with milvexian; in particular, such effects have been observed with itraconazole and diltiazem in observational studies, and potential drug-drug interactions with midazolam, rifampicin, verapamil, and ketoconazole have also been reported. 98,99…”

Drug–Drug Interactions of FXI Inhibitors: Clinical Relevance

“…Similar DDI clinical studies have been performed with milvexian, where the effect of rifampicin (CYP3A4 and P-gp inducer) and two CYP450 inhibitors (itraconazole (strong) and diltiazem (moderate)) on the pharmacokinetic of milvexian were investigated ( Table 6 ) [ 53 , 54 ].…”

Determination of the Potential Clinical Benefits of Small Molecule Factor XIa Inhibitors in Arterial Thrombosis

“…The half-life of milvexian was slightly longer (∼18 h) in patients with moderate (eGFR from ≥30 to ≤59 mL/min/1.73 m 2 ) and severe (eGFR < 30 mL/min/1.73 m 2 ) renal impairment . Milvexian is a substrate for CYP3A4 (Table ) and P-glycoprotein (P-gp). , Milvexian exposure was moderately increased following concomitant use with multiple doses of itraconazole (a strong CYP3A4 and P-gp inhibitor) but was slightly increased following multiple doses of diltiazem (a moderate CYP3A4 inhibitor) . Notably, a substantial decrease in milvexian exposure was observed after coadministration with multiple doses of rifampin, a potent CYP3A4 and P-gp inducer .…”