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

Antithrombotic therapies are routinely used for the prevention of thrombosis in patients with cardiovascular disease and are increasingly used as a prophylaxis following orthopedic surgeries for the prevention of deep-vein thrombosis and pulmonary embolism [1‐5]. Despite a well-demonstrated effectiveness, there are challenges with the use of current therapies, such as residual risk of ischemic events and the risk of bleeding episodes [6‐9]. As such, the development of a novel anticoagulant with an improved risk–benefit profile for bleeding episodes compared with current agents would fulfill an unmet medical need.

The coagulation cascade involves the coordinated activation of plasma proteases, their co-factors, and platelets, through two distinct coagulation pathways, which in total balance clot formation and dissolution [10]. The zymogen factor XI (FXI) is a component of the intrinsic contact pathway and, when activated by thrombin to the protease FXIa, enhances the formation and the stability of clots. FXIa also amplifies thrombin generation when coagulation is initiated by either tissue factor or thrombin, forming a positive feedback loop for coagulation [11, 12]. Notably, epidemiologic data suggest that FXIa plays a greater role in thrombosis than in hemostasis, suggesting that inhibition of FXI or FXIa would be beneficial for thrombosis prevention, without increasing the risk of bleeding in a variety of conditions that predispose individuals to a high risk of thrombotic events [13, 14]. In both clinical and preclinical studies, FXIa inhibitors have been shown to reduce thrombus formation [15‐18].

Milvexian (BMS-986177/JNJ-70033093) is a potent, orally bioavailable small molecule that inhibits FXIa with high affinity and selectivity [19]. In preclinical models of arterial and venous thrombosis, milvexian demonstrated antithrombotic activity while preserving homeostasis [20, 21]. In subsequent clinical studies, milvexian was generally safe and well tolerated in healthy participants and in those with hepatic and renal impairment [22‐24].

Elimination of milvexian occurs across multiple pathways, including cytochrome P450 (CYP)–mediated metabolism. Preclinical results indicate that milvexian is a substrate of CYP3A4/5 and is also a substrate for P-glycoprotein (P-gp; unpublished data). CYP3A4/5 is involved in the metabolism of a wide range of pharmacological therapies [25]. Therapies that are metabolized by CYP3A4/5 can be impacted by concomitant drugs that are inducers or inhibitors of CYP3A4/5, creating clinically relevant pharmacokinetic (PK) effects [26]. Similarly, P-gp is an ATP-binding cassette transporter that plays a role in drug absorption and disposition [27]. Understanding the effects of CYP3A and/or P-gp inhibition on the PK and pharmacodynamic (PD) properties of milvexian will help to characterize the human metabolic profile and inform dosing strategies in patients taking co-medications that are CYP3A and/or P-gp inhibitors.

This study assessed the effects of strong and moderate CYP3A inhibition with itraconazole and diltiazem, respectively, on the PK and PD properties of milvexian. Itraconazole is considered a strong index inhibitor of CYP3A4/5 [28] and can cause ≥ 10-fold increase in the area under the curve (AUC) of sensitive substrates. Itraconazole is also an inhibitor for P-gp and has demonstrated a > 1.25-fold increase in the AUC of digoxin [28]. Investigation of drug–drug interaction (DDI) of itraconazole with milvexian will model a maximum effect of both CYP3A and P-gp inhibition. The bioavailability of itraconazole (oral solution) is greater under fasted conditions and provides a higher systemic exposure with less variability. As such, participants receiving itraconazole in the current study fasted overnight on the day of co-administration of itraconazole and milvexian. A dosing regimen of 200 mg of itraconazole with a 3-day run-in before co-administration with the substrate was chosen for the sequence, as the lead-in allows for accumulation, greater itraconazole exposure, and a potentially greater degree of CYP3A inhibition [29]. Diltiazem is considered a moderate inhibitor of CYP3A4 and has increased the AUC of certain sensitive CYP3A substrates more than fivefold [28]. To investigate the potential for DDI between moderate CYP3A inhibitors and milvexian, diltiazem was co-administered with milvexian. Diltiazem is well absorbed from the gastrointestinal tract and is subject to an extensive first-pass effect, giving an absolute oral bioavailability (compared to intravenous administration) of about 40% [30]. To evaluate the potential interaction, a 240-mg daily dose of diltiazem was selected for the current study, as this dose is commonly used in clinical practice and has been used in previous studies [30, 31]. Based on preclinical in vitro studies, the potential of milvexian to cause clinically relevant DDIs with substrates of CYP enzymes or P-gp transport at the dose investigated was considered to be low. Therefore, the effect of itraconazole and diltiazem on milvexian, but not the effect of milvexian on itraconazole and diltiazem exposure, was investigated in this study.

The aim of the current study was to characterize PK parameters of a single dose of milvexian alone and in combination with either itraconazole or diltiazem in healthy participants, with secondary assessments in measurements of aPTT, safety, and tolerability.

Overall, results from this study were consistent with those of prior preclinical studies that showed that milvexian is a substrate for CYP3A and P-gp. Mean C_max, AUC_(0–T), AUC_(INF), and C₂₄ were increased when milvexian was co-administered with a strong (itraconazole) or moderate (diltiazem) CYP3A inhibitor. The impact of a strong CYP3A inhibitor was confirmed to be < 5-fold by the observed increases in milvexian exposure, and the impact of a moderate CYP3A inhibitor was confirmed to be less than 2.5-fold by the increases in milvexian exposure, which suggests that milvexian would not be considered a sensitive CYP3A substrate (i.e., AUC ≥ 5-fold) [28]. The median T_max of milvexian was not altered by co-administration of itraconazole or diltiazem, but the mean T_1/2 was longer with co-administration of itraconazole, which suggests reduced clearance. The slight increase in C_max (approximately 28%; Fig. 3) was consistent with a modest effect of itraconazole on P-gp or first-pass metabolism. Increases in milvexian exposure after co-administration with itraconazole or diltiazem may not be substantial enough to require dose changes with inhibitors of CYP3A/P-gp; further data from ongoing phase 2 clinical trials are needed to help determine whether milvexian dose adjustments will be required for patients taking concomitant inhibitors of CYP3A and/or P-gp.

The mean aPTT was prolonged after dosing of milvexian in both the itraconazole and diltiazem sequences. In general, higher values of aPTT were associated with higher concentrations of milvexian. Moreover, the apparent relationship between aPTT and milvexian concentrations was similar for milvexian alone or in the presence of itraconazole or diltiazem; this observation was consistent with expectations that itraconazole or diltiazem alone would not have an effect on aPTT.

The results from this study indicate that milvexian has a similar CYP3A and/or P-gp inhibition profile as several of the Factor Xa inhibitors, namely rivaroxaban and apixaban [32]. However, given the potentially improved therapeutic window of milvexian, the same restrictions on co-medications and dose adjustment needed for factor Xa inhibitors may not apply. Further studies, including the radiolabeled mass-balance to characterize the absorption, distribution, metabolism, and excretion (ADME) profile of milvexian, and patient studies to characterize the risk-benefit profile, will help with the comparison of milvexian to factor Xa inhibitors.

The study was somewhat limited by the sample sizes in each panel; however, the CIs around the GMR indicate that a meaningful conclusion can be drawn from these results. Further characterization of the impact of co-medications with CYP3A and/or P-gp inhibition will be generated through development of population PK models and exposure–response analysis from broader patient studies. Of note, both a moderate and a strong CYP inhibitor were selected for investigation in the current study. Future patients may be exposed to both strong and moderate CYP inhibitors, thus necessitating the investigation of the effects of CYP inhibition on the PK of milvexian. In addition, these results will contribute to future modeling efforts. Overall, findings from the current study suggest that a dose adjustment of milvexian may not be necessary for patients receiving concomitant CYP3A and/or P-gp inhibitors.

In conclusion, PK assessments demonstrated an increase in milvexian exposure as a function of co-administration with moderate and strong CYP3A inhibitors, indicating that milvexian is a substrate for CYP3A. Milvexian administration also resulted in concentration-related prolongation of aPTT, with higher aPTT values observed at higher milvexian concentrations. Administration of a single dose of milvexian alone and in combination with itraconazole or diltiazem was generally safe and well tolerated by the healthy participants in this study.