Single-Dose Pharmacokinetics of Milvexian in Participants with Normal Renal Function and Participants with Moderate or Severe Renal Impairment

Perera, Vidya; Abelian, Grigor; Li, Danshi; Wang, Zhaoqing; Zhang, Liping; Lubin, Susan; Bello, Akintunde; Murthy, Bindu

doi:10.1007/s40262-022-01150-1

Cited by 12 publications

(5 citation statements)

References 44 publications

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“…Compared with those with healthy renal function (13.8 h), the half-life was longer in subjects with moderate (18.0 h) or serious (17.7 h) renal disorders. This showed that Milvexian is safe and well tolerated in people with renal dysfunction [ 37 ]. A dose-exploration trial of Milvexian examined the tolerability, safety, PD and PK characteristics of sequential single incremental doses (SADs) and multiple incremental doses (MADs).…”

Section: Resultsmentioning

confidence: 99%

Factor XIa Inhibitors as a Novel Anticoagulation Target: Recent Clinical Research Advances

Xia

Tang

2023

Pharmaceuticals

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Background: While current clinically administered anticoagulant medications have demonstrated effectiveness, they have also precipitated significant risks: severe bleeding complications including, but not limited to, gastrointestinal hemorrhaging and intracranial and other life-threatening major bleedings. An ongoing effort is being made to identify the best targets for anticoagulant-targeted drugs. Coagulation factor XIa (FXIa) is emerging as an important target of current anticoagulant treatment. Objective: This review will summarize the development of anticoagulants and recent advances in clinical trials of experimental factor XI inhibitors from a clinical application perspective. Results: As of 1 January 2023, our search screening included 33 clinical trials. We summarized the research progress of FXIa inhibitors from seven clinical trials that evaluated their efficacy and safety. The results showed no statistically meaningful distinction in the primary efficacy between patients receiving FXIa inhibitors compared to controls (RR = 0.796; 95% CI: 0.606–1.046; I2 = 68%). The outcomes did not indicate a statistical difference in the occurrence of any bleeding between patients receiving FXIa inhibitors compared to controls (RR = 0.717; 95% CI: 0.502–1.023; I2 = 60%). A subgroup analysis found significant differences in severe bleeding and clinically relevant hemorrhaging in subjects receiving FXIa inhibitors compared to Enoxaparin (RR = 0.457; 95% CI: 0.256–0.816; I2 = 0%). Conclusions: Clinical trials to date have indicated that factor XIa is a potential anticoagulation target, and factor XIa inhibitors may play an important role in the development of anticoagulants.

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Section: Resultsmentioning

confidence: 99%

Factor XIa Inhibitors as a Novel Anticoagulation Target: Recent Clinical Research Advances

Xia

Tang

2023

Pharmaceuticals

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“…The total exposure to milvexian, after a single oral 60 mg dose, was 41% and 54% greater in participants with eGFR values of 30 and 15 mL/min/1.73 m 2 , respectively, than in subjects with normal renal function. The median time to maximum concentration (T max ) was similar for the three groups (4.5–5.0 h), and the half-life increased for participants with moderate (18.0 h) or severe (17.7 h) renal impairment compared with those with normal renal function (13.8 h) [ 43 ]. Thus, according to the low renal excretion, a single dose of milvexian 60 mg was safe and well tolerated in participants with moderate or severe renal impairment [ 43 ].…”

Section: Doac and Small Drug Molecules Anti Fxia: Potential Differenc...mentioning

confidence: 99%

“…The median time to maximum concentration (T max ) was similar for the three groups (4.5–5.0 h), and the half-life increased for participants with moderate (18.0 h) or severe (17.7 h) renal impairment compared with those with normal renal function (13.8 h) [ 43 ]. Thus, according to the low renal excretion, a single dose of milvexian 60 mg was safe and well tolerated in participants with moderate or severe renal impairment [ 43 ].…”

Section: Doac and Small Drug Molecules Anti Fxia: Potential Differenc...mentioning

confidence: 99%

“…Another level of differentiation between the DOAC and the new oral anti FXIa is the renal excretion. Milvexian and asundexian are marginally eliminated by the kidney and thus can be potentially administered in patients with moderate or severe renal impairment ( Table 2 ), as documented by the results of a clinical trial [ 43 ].…”

Section: Doac and Small Drug Molecules Anti Fxia: Potential Differenc...mentioning

confidence: 99%

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Drug–Drug Interactions of FXI Inhibitors: Clinical Relevance

Ferri,

Colombo,

Corsini

2024

Hematology Reports

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Inhibitors of the factor FXI represent a new class of anticoagulant agents that are facing clinical approval for the treatment of acute coronary syndrome (ACS), venous thromboembolism (VTE), and stroke prevention of atrial fibrillation (AF). These new inhibitors include chemical small molecules (asundexian and milvexian), monoclonal antibodies (abelacimab, osocimab, and xisomab), and antisense oligonucleotides (IONIS-FXIRX and fesomersen), and thus, they have very peculiar and different pharmacokinetic and pharmacodynamic properties. Besides their clinical efficacy and safety, based on their pharmacological heterogeneity, the use of these drugs in patients with comorbidities may undergo drug–drug interactions (DDIs) with other concomitant therapies. Although only little clinical evidence is available, it is possible to predict clinically relevant DDI by taking into consideration their pharmacokinetic properties, such as the CYP450-dependent metabolism, the interaction with drug transporters, and/or the route of elimination. These characteristics may be useful to differentiate their use with the direct oral anticoagulant (DOAC) anti -FXa (rivaroxaban, apixaban, edoxaban) and thrombin (dabigatran), whose pharmacokinetics are strongly dependent from P-gp inhibitors/inducers. In the present review, we summarize the current clinical evidence on DDIs of new anti FXI with CYP450/P-gp inhibitors and inducers and indicate potential differences with DOAC anti FXa.

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“… 91 Higher doses (200 or 500 mg) appeared to prolong the aPTT for over 24 h. 91 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. 92 Milvexian is a substrate for CYP3A4 ( Table 1 ) and P-glycoprotein (P-gp). 93 , 94 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).…”

Section: Milvexianmentioning

confidence: 99%

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

Wichaiyo

Parichatikanond

Visansirikul

et al. 2023

ACS Pharmacol. Transl. Sci.

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Anticoagulants are the mainstay for the prevention and treatment of thrombosis. However, bleeding complications remain a primary concern. Recent advances in understanding the contribution of activated factor XI (FXIa) in arterial thrombosis with a limited impact on hemostasis have led to the development of several FXIa-targeting modalities. Injectable agents including monoclonal antibodies and antisense oligonucleotides against FXIa have been primarily studied in venous thrombosis. The orally active small molecules that specifically inhibit the active site of FXIa are currently being investigated for their antithrombotic activity in both arteries and veins. This review focuses on a discussion of the potential clinical benefits of small molecule FXIa inhibitors, mainly asundexian and milvexian, in arterial thrombosis based on their pharmacological profiles and the compelling results of phase 2 clinical studies. The preclinical and epidemiological basis for the impact of FXIa in hemostasis and arterial thrombosis is also addressed. In recent clinical study results, asundexian appears to reduce ischemic events in patients with myocardial infarction and minor-to-moderate stroke, whereas milvexian possibly provides benefits in patients with minor stroke or high-risk transient ischemic attack (TIA). In addition, asundexian and milvexian had a minor impact on hemostasis even in combination with dual-antiplatelet therapy. Other orally active FXIa inhibitors also produce antithrombotic activity in vivo with low bleeding risk. Therefore, FXIa inhibitors might represent a new class of direct-acting oral anticoagulants (DOACs) for the treatment of thrombosis, although the explicit clinical positions of asundexian and milvexian in patients with ischemic stroke, high-risk TIA, and coronary artery disease require confirmation from the outcomes of ongoing phase 3 trials.

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Single-Dose Pharmacokinetics of Milvexian in Participants with Normal Renal Function and Participants with Moderate or Severe Renal Impairment

Cited by 12 publications

References 44 publications

Factor XIa Inhibitors as a Novel Anticoagulation Target: Recent Clinical Research Advances

Factor XIa Inhibitors as a Novel Anticoagulation Target: Recent Clinical Research Advances

Drug–Drug Interactions of FXI Inhibitors: Clinical Relevance

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

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