Factor Xa Inhibitors

2006 ◽  
Author(s):  
Richard C. Becker ◽  
Frederick A. Spencer
Keyword(s):  
Renal Impairment ◽  
Early Stage ◽  
Severe Renal Impairment ◽  
Subcutaneous Administration ◽  
Factor Xa ◽  
Drug Clearance ◽  
Factor Xa Inhibitors ◽  
Thromboembolism Prophylaxis ◽  
Mild Renal Impairment ◽  
St Segment Elevation

The importance of factor Xa in the initiation and propagation of coagulation, as well as its pluripotential cellular properties, has been discussed previously. Considered collectively, the effects exhibited by this particular protease make it an attractive target for pharmacologic inhibition. Factor Xa inhibition can be classified and subcategorized as follows: indirect (antithrombin [AT]-dependent), nonselective (e.g., unfractionated heparin); indirect, semi-selective (e.g., low-molecular-weight heparin); indirect, selective (e.g., fondaparinux); and direct, selective (e.g., DX-9065a [in early stage of development]). Oral factor Xa inhibitors are in phase II testing. Fondaparinux (Arixtra) is a synthetic pentasaccharide that requires AT for selective fXa binding (Petitou et al., 1991). Unlike heparin compounds, fondaparinux does not inhibit thrombin directly nor does it interact with platelets (or platelet-derived proteins). After subcutaneous administration in healthy volunteers, fondaparinux was nearly 100% bioavailable, and absorption was rapid (Cmax within 2 hours) (Donat et al., 2002). Clearance is through renal mechanisms with a terminal halflife of 17 ± 3 hours (slightly longer in elderly volunteers). Overall, drug clearance is 25% lower in patients with mild renal impairment (creatinine clearance [CrCl] 50–80 mL/min), approximately 40% lower in patients with moderate renal impairment (CrCl 30–50 mL/min), and 55% lower in patients with severe renal impairment (CrCl <30 mL/min). OASIS-5, the largest trial performed to date in non-ST segment elevation acute coronary syndromes (ACS), randomized 20,078 patients to fondaparinux (2.5 mg subcuaneous once daily) or enoxaparin (1 mg/kg twice daily) for 2 to 8 days. The primary outcome (composite of death, MI, and refractory ischemia on day 9) was 5.9% and 5.8%, respectively. Major bleeding rates were 2.1% and 4.0%, respectively (hazard ratio 0.53; p<.001). By 6-month follow-up, the endpoints of death, death/MI, stroke, and composite of death/MI/stroke were significantly reduced in those receiving fondaparinux. Catheter thrombosis (during PCI) was 3-fold higher in fondaparinux-treated patients compared to those receiving enoxaparin (1.3% vs. 0.5%, respectively) (European Society of Cardiology presentation, September 2005). The clinical use of fondaparinux for venous thromboembolism prophylaxis will be discussed in Chapter 22.

Persistent Rivaroxaban Effect Due to Impaired Renal Clearance and Medication Effects

2019 ◽  
Author(s):  
Chelsea Milito ◽  
Hannah McRae ◽  
Adrienne Victor ◽  
Majed A Refaai ◽  
Amy E Schmidt
Keyword(s):  
Renal Function ◽  
Renal Impairment ◽  
Renal Clearance ◽  
Active Site ◽  
Severe Renal Impairment ◽  
Factor Xa ◽  
Direct Oral Anticoagulant ◽  
Medication List ◽  
Mild Renal Impairment ◽  
Medication Effects

Abstract Rivaroxaban (Xarelto; Johnson & Johnson Services, Inc) is a direct oral anticoagulant (DOAC) that works by directly inhibiting the active site of factor Xa (FXa). Rivaroxaban is metabolized and cleared via the kidney and liver. The results of various studies have shown that patients with severe renal impairment should receive reduced dosages of rivaroxaban or another anticoagulant due to impaired clearance. Although it is not required, monitoring rivaroxaban is useful in some conditions; however, the assays required for such monitoring are not readily available. Herein, we present a case of a 68-year-old Caucasian male patient who was receiving rivaroxaban (20 mg/day) for atrial flutter and had mild renal impairment. The patient was found to have increased effect of rivaroxaban due to further impairment of renal clearance caused by several renally cleared medications. This case highlights the importance of closely examining the renal function of and medication list for a patient before starting DOACs such as rivaroxaban.

scholarly journals Pharmacokinetics of Telbivudine in Subjects with Various Degrees of Renal Impairment

2007 ◽  
Vol 51 (12) ◽  
pp. 4231-4235 ◽  
Author(s):  
Xiao-Jian Zhou ◽  
Suzanne Swan ◽  
William B. Smith ◽  
Thomas C. Marbury ◽  
Gloria Dubuc-Patrick ◽  
...  
Keyword(s):  
Renal Function ◽  
Renal Impairment ◽  
Normal Renal Function ◽  
Severe Renal Impairment ◽  
Normal Function ◽  
Plasma Exposure ◽  
Mild Renal Impairment ◽  
Severe Impairment ◽  
Stage Renal Disease ◽  
End Stage

ABSTRACT This study evaluates the effect of renal impairment on the pharmacokinetics of telbivudine. Thirty-six subjects were assigned, on the basis of creatinine clearance (CLCR), to 1 of 5 renal function groups with 6 to 8 subjects per group: normal renal function; mild, moderate, or severe renal impairment; or end-stage renal disease [ESRD] requiring hemodialysis. Subjects received a single oral dose of telbivudine at 600 mg (normal function and mild impairment), 400 mg (moderate impairment), or 200 mg (severe impairment and ESRD); plasma and/or urine samples were collected over a 48-h period for pharmacokinetic analyses. Telbivudine was well tolerated by all subjects. The pharmacokinetics of 600 mg of telbivudine were comparable for subjects with mild renal impairment and normal renal function. Likewise, for subjects with moderate to severe impairment, including ESRD, reduced doses from 200 to 400 mg produced plasma exposure similar to that for subjects with normal renal function. These results indicate that the pharmacokinetics of telbivudine were dependent on renal function, especially for subjects with moderate to severe renal impairment or ESRD. Apparent total plasma clearance, renal clearance (CLR), and urinary excretion of telbivudine decreased as renal function deteriorated. A linear relationship was established between CLR and CLCR. In ESRD subjects, a routine 3.5- to 4-h hemodialysis session removed telbivudine from plasma at an extraction ratio of ∼45%, representing a ∼23% reduction in total exposure. These results suggest that while no adjustment of the telbivudine dose appears necessary for subjects with mild renal impairment, dose adjustment is warranted for those with moderate to severe renal impairment or ESRD in order to achieve optimal plasma exposure.

scholarly journals Venous Thromboembolism Prophylaxis After TKA: Aspirin, Warfarin, Enoxaparin, or Factor Xa Inhibitors?

2017 ◽  
Vol 475 (9) ◽  
pp. 2205-2213 ◽  
Author(s):  
Abiram Bala ◽  
James I. Huddleston ◽  
Stuart B. Goodman ◽  
William J. Maloney ◽  
Derek F. Amanatullah
Keyword(s):  
Venous Thromboembolism ◽  
Factor Xa ◽  
Factor Xa Inhibitors ◽  
Thromboembolism Prophylaxis ◽  
Venous Thromboembolism Prophylaxis

Effects of Renal Impairment on the Pharmacology of Rivaroxaban (BAY 59-7939) - An Oral, Direct, Factor Xa Inhibitor.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 913-913 ◽  
Author(s):  
Atef Halabi ◽  
Haidar Maatouk ◽  
Norbert Klause ◽  
Volkmar Lufft ◽  
Dagmar Kubitza ◽  
...  
Keyword(s):  
Renal Impairment ◽  
Dose Adjustment ◽  
Severe Renal Impairment ◽  
Plasma Concentrations ◽  
Factor Xa ◽  
Direct Factor ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Control Subjects ◽  
Severe Impairment ◽  
Mild Impairment

Abstract Rivaroxaban (BAY 59-7939) is an oral, direct Factor Xa (FXa) inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. It has predictable pharmacokinetics and pharmacodynamics in healthy subjects. Approximately 30% of rivaroxaban is excreted unchanged in the urine; therefore, renal excretion is an important route of elimination. This multicenter study was performed to evaluate the effect of renal impairment on the tolerability, pharmacokinetics, and pharmacodynamics of a single oral 10 mg dose of rivaroxaban. Subjects (N=32) were allocated to one of four groups (matched by age and gender), based on calculated creatinine clearance (CrCL): ≥80 mL/min (control); 50–79 mL/min (mild impairment); 30–49 mL/min (moderate impairment); and <30 mL/min (severe impairment). Rivaroxaban was well tolerated; treatment-emergent adverse events occurred in 62.5% of control subjects, and 12.5%, 12.5%, and 37.5% of those with mild, moderate, and severe renal impairment, respectively. All adverse events were mild to moderate in severity, and resolved by the end of the study. Decreased CrCL led to increased rivaroxaban plasma concentrations: AUC was 44%, 52%, and 64% higher in subjects with mild, moderate, and severe renal impairment, respectively, compared with control subjects (p<0.05); Cmax was relatively unaffected, and tmax was delayed in subjects with CrCL <50 mL/min (3 hours vs 2 hours for control). Renal clearance of rivaroxaban decreased with decreasing renal function; 29% of rivaroxaban was excreted via the urine in control subjects, compared with 20%, 13%, and 10% in those with mild, moderate, and severe renal impairment, respectively. The pharmacodynamic effects of rivaroxaban (inhibition of FXa activity and prolongation of prothrombin time [PT]) were increased with decreasing renal function. The AUC for inhibition of FXa activity increased by 50% (mild impairment), 86% (moderate impairment), and 100% (severe impairment) (p<0.01; Pearson’s correlation coefficient −0.49), and the AUC for prolongation of PT increased by 33%, 116%, and 144%, respectively (p<0.001; correlation −0.56), compared with control. The maximum effects (Emax) of rivaroxaban on inhibition of FXa activity or prolongation of PT did not differ to a relevant extent among the different groups. In conclusion, rivaroxaban plasma concentrations and, as a result, inhibition of FXa activity and prolongation of PT, are inversely correlated with CrCL. In phase II clinical studies of rivaroxaban, patients with mild or moderate renal impairment were included without dose adjustment. However, whether dose adjustment is necessary in patients with renal impairment will require investigation in future clinical trials.

scholarly journals Impact of Renal Function on the Pharmacokinetics and Safety of Ceftolozane-Tazobactam

2014 ◽  
Vol 58 (4) ◽  
pp. 2249-2255 ◽  
Author(s):  
Myra Wooley ◽  
Benjamin Miller ◽  
Gopal Krishna ◽  
Ellie Hershberger ◽  
Gurudatt Chandorkar
Keyword(s):  
Renal Function ◽  
Renal Impairment ◽  
Severe Renal Impairment ◽  
Moderate Renal Impairment ◽  
Open Label ◽  
Two Phase ◽  
Time Curve ◽  
Mild Renal Impairment ◽  
Before And After ◽  
Stage Renal Disease

ABSTRACTCeftolozane-tazobactam is a novel antipseudomonal cephalosporin with a β-lactamase inhibitor. We investigated the pharmacokinetics (PK) and safety of ceftolozane-tazobactam in subjects with various degrees of renal function. In two phase I, open-label studies, a single dose of ceftolozane-tazobactam was administered as a 1-h intravenous infusion to 24 subjects with normal, mild, or moderate renal impairment (1,000/500 mg) and six subjects with severe renal impairment (500/250 mg). Six subjects with end-stage renal disease (ESRD) received two doses of ceftolozane-tazobactam (500/250 mg each), pre- and posthemodialysis (post-HD). PK parameters were determined by noncompartmental methods. Plasma exposure to ceftolozane-tazobactam increased as renal function declined with only slightly increased exposures in subjects with mild renal impairment; the median area under the concentration-time curve from time zero to infinity (AUC0-∞) for ceftolozane and tazobactam increased 1.4- and 1.2-fold, respectively. In subjects with moderate renal impairment, the AUC0-∞increased 2.5- and 2.2-fold for ceftolozane and tazobactam, respectively. In subjects with severe renal impairment, the dose-normalized median AUC0-∞for ceftolozane and tazobactam increased 4.4- and 3.8-fold, respectively. In ESRD subjects, ceftolozane and tazobactam concentrations declined rapidly following the start of HD, with approximately 66 and 56% reductions in overall exposure based on the AUC0-∞before and after dialysis. Slight increases in exposure with mild renal impairment do not warrant a dose adjustment; however, subjects with moderate or severe renal impairment and those on HD require a decrease in the dose, a change in the frequency of administration, or both to achieve exposures within the established safety and efficacy margins of ceftolozane-tazobactam. Ceftolozane-tazobactam was well tolerated by all renal impairment groups.

State-of-the-Art Review: Factor Xa Versus Factor IIa Inhibitors

1997 ◽  
Vol 3 (1) ◽  
pp. 16-24 ◽  
Author(s):  
Brigitte Kaiser
Keyword(s):  
Early Stage ◽  
Thrombus Formation ◽  
Biological Effects ◽  
Experimental Studies ◽  
Factor Xa ◽  
Thrombin Inhibitors ◽  
Factor Xa Inhibitors ◽  
Coagulation Cascade ◽  
Antithrombotic Agents ◽  
Wide Range

The development of specific inhibitors of blood coagulation enzymes has led to a number of new anticoagulant/antithrombotic agents that could be useful for prophylaxis and/or treatment of thromboembolic disorders. Because thrombin is the central bioregulatory enzyme in hemostasis, blocking of the active site of the enzyme by a fast reaction with an inhibitor may effectively prevent intravascular coagulation as well as other important biological effects of thrombin. For the direct inactivation of thrombin, several classes of compounds have been developed and characterized in vitro and in vivo as potential antithrombotic agents including naturally occurring as well as synthetic thrombin inhibitors such as hirudin, hirulog, arginine (argatroban), and benzamidine (NAPAP) derivatives as well as tripeptide-type inhibitors (efegatran, D-Phe-Pro-Arg-CH2Cl, boroarginine derivatives). Experimental findings suggest that directly acting thrombin inhibitors may be effective in a wide range of arterial and venous thrombotic events. The important role of factor Xa in the coagulation cascade at the stage of the conversion of extrinsic and intrinsic pathways and the amplification of its procoagulant action by prothrombinase complex formation makes factor Xa a promising target also for antithrombotic drugs. Experimental studies on highly effective and selective factor Xa inhibitors (antistasin, tick anticoagulant peptide, yagin, DX-9065a) showed that inhibition of coagulation at a relatively early stage is a very effective way for the prevention of thrombotic processes. Furthermore, it is assumed that factor Xa inhibitors selectively inhibit thrombus formation without compromising hemostasis. In conclusion, both thrombin and factor Xa inhibitors are promising drugs for the management of thrombotic disorders. However, besides the strong inhibitory potency against the target enzyme, other pharmacological aspects such as pharmacodynamics, pharmacokinetics, and toxic side effects must be included in the evaluation of the potential usefulness of thrombin and factor Xa inhibitors for clinical indications. Key Words: Anticoagulants—Antithrombotics—Factor Xa inhibitors—Thrombin inhibitors.

Hypertensive urgencies and emergencies

2020 ◽  
pp. 3800-3810
Author(s):  
Gregory Y.H. Lip ◽  
Alena Shantsila
Keyword(s):  
Blood Pressure ◽  
Renal Impairment ◽  
Severe Renal Impairment ◽  
Rare Condition ◽  
Visual Disturbance ◽  
Organ Damage ◽  
Renal Diseases ◽  
Mild Renal Impairment ◽  
Cotton Wool Spots ◽  
Hypertensive Urgencies

Hypertensive urgencies and emergencies occur most commonly in patients with previous hypertension, especially if inadequately managed. About 40% of cases have an underlying cause, most commonly renovascular disease, primary renal diseases, phaeochromocytoma, and connective tissue disorders. Hypertensive emergencies occur when severely elevated or sudden marked increase in blood pressure is associated with acute end-organ damage. Malignant phase hypertension is a rare condition characterized by very high blood pressure, with bilateral retinal haemorrhages and/or exudates or cotton wool spots, with or without papilloedema. Presentation is typically with visual disturbance, with or without headaches. Urinalysis may demonstrate proteinuria and haematuria, even in the absence of primary renal disease. Some patients with mild renal impairment at first presentation may improve, or even regain normal renal function, but this is unlikely to occur in those with more severe renal impairment at presentation.

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