Praxbind: Antagonist of the anticoagulant effect of dabigatran

2021-06-21 03:36 AM

Praxbind is a specific anticoagulant of dabigatran and is indicated for patients treated with Pradaxa (dabigatran) when rapid reversal of the anticoagulant effect of dabigatran is required.

Producer

Boehringer Ingelheim

Ingredient

Each vial: Idarucizumab 2.5g.

Describe

The clear or slightly colored solution, colorless to pale yellow.

Pharmacodynamic

Pharmacotherapeutic group: all other therapeutic medicinal products, specific antidotes.

ATC code: V03AB37.

Mechanism of action

Idarucizumab is a specific antidote to dabigatran. The drug is a human monoclonal antibody (Fab) fragment that binds to dabigatran with very high affinity, approximately 300 times the binding affinity of dabigatran to thrombin. The idarucizumab- dabigatran complex is characterized by a very fast binding rate and a very slow rate of dissociation resulting in a very stable complex. Idarucizumab has strong and specific binding to dabigatran and its metabolites, thereby neutralizing the anticoagulant effects of these drugs.

Clinical trials

Three randomized, double-blind, placebo-controlled phase I clinical studies in 283 subjects (224 patients treated with idarucizumab) were performed to evaluate safety, efficacy, tolerability, and pharmacokinetics. pharmacokinetics and pharmacodynamics of idarucizumab, alone or after dabigatran etexilate. The study population consisted of healthy individuals and these individuals were subdivided into population-specific groups by age, weight, race, sex, and renal impairment. In these studies, the dose of idarucizumab ranged from 20 mg to 8 g and the infusion time ranged from 5 minutes to 1 hour.

Characteristic values ​​for pharmacokinetic and pharmacodynamic parameters were established based on a group of healthy subjects aged 45-64 years who received 5 g of idarucizumab.

A prospective, open-label, randomized, uncontrolled study (RE-VERSE AD) was performed to evaluate the treatment of adult patients treated with dabigatran with life-threatening bleeding. fatal or uncontrolled (group A) or patients requiring emergency surgery or urgent procedure (group B). The primary endpoint was the percentage maximal resolution of the anticoagulant effect of dabigatran within 4 hours of administration of idazucirumab, based on the determination of the primary laboratory parameter dilution thrombin time (dTT) or ecarin coagulation time ( ECT). The primary secondary endpoint was a restoration of hemostasis.

RE-VERSE AD included data from 503 patients: 301 patients with major bleeding (group A), 202 patients requiring urgent surgery/procedure (group B). Approximately half of the patients in each group were male. The mean age was 78 years and the mean creatinine clearance was 52.6 mL/min. Approximately 61.5% of patients in group A and 62.4% of patients in group B were being treated with dabigatran 110 mg twice daily.

Reversal effects were evaluated only in patients with prolonged clotting time prior to treatment with idarucizumab. The majority of patients, in both groups A and B, showed complete resolution of the anticoagulant effect of dabigatran (dTT: 98.7%; ECT: 82.2%; aPTT: 92.5%, respectively, on evaluable patients) during the first 4 hours after administration of 5g of idarucizumab. The reverse effect appears immediately after taking the drug.

Hemostasis was restored in 80.3% of patients with evaluable major bleeding and complete hemostasis was observed in 93.4% of patients requiring the urgent procedure.

Total 503 patients, 101 patients died; Each of these deaths could be attributed to complications of the primary event or to association with comorbidities. Thrombotic events were reported in 34 patients (23 out of 34 patients were not on anticoagulation at the time of the event) and in each case, the thrombotic event was probably due to a comorbid condition. of the patient. Mild symptoms of potential hypersensitivity (fever, bronchospasm, hyperventilation, rash, or pruritus) have been reported. A causal relationship with idarucizumab has not been established.

Pharmacodynamic effects

The pharmacokinetics of idarucizumab following administration of dabigatran etexilate were studied in healthy volunteers aged 45 to 64 years receiving a dose of 5 g intravenously. The mean peak concentrations of dabigatran in healthy volunteers were within the range of patients receiving dabigatran etexilate 150 mg twice daily.

Effect of idarucizumab on anticoagulant effect and circulating dabigatran concentration

Immediately following administration of idarucizumab, plasma concentrations of unbound free dabigatran were reduced by more than 99% to the point where the concentrations were no longer anticoagulant.

In the majority of patients, a resolution of dabigatran plasma concentrations was observed for up to 12 hours (≥ 90%). In a subgroup of patients, a return of unbound plasma dabigatran was observed and a concomitant increase in coagulation tests was observed, possibly due to peripheral redistribution of dabigatran. . This occurred 1-24 h after administration of idarucizumab mainly at 12 h.

Dabigatran prolongs the clotting time of markers of coagulation such as thrombin dilution time (dTT), thrombin time (TT), activated partial thromboplastin time (aPTT), and ecarin coagulation time. ECT), these are indicators that help to reflect the relative anticoagulation level. Values ​​within the normal range after administration of idarucizumab indicate that there is no longer an anticoagulant effect in the patient's body. Above-normal values ​​may be due to residual effects of dabigatran or other clinical conditions such as the presence of other drugs or infusion-induced coagulation disorders. These tests are used to evaluate the anticoagulant effect of dabigatran. A complete and sustained prolongation of the clotting time of dabigatran was observed immediately after infusion of idarucizumab and persisted over the entire observation period for at least 24 hours.

Thrombin formation parameters

Dabigatran markedly affects endogenous thrombin (ETP) activity. Treatment with idarucizumab resulted in both the time to thrombin latency and the time to peak return to baseline as determined 0.5 to 12 hours after discontinuation of the idarucizumab infusion. Idarucizumab alone had no anticoagulant effect as determined by the ETP value. This indicates that idarucizumab has no effect on blood clotting.

Dabigatran etexilate reuse

24 h after infusion of idarucizumab, re-administration of dabigatran etexilate resulted in the expected anticoagulant effect.

Immunogenicity

Serum samples from 283 subjects in phase I trials (224 volunteers treated with idarucizumab) and 501 patients tested for anti-idarucizumab antibodies before and after treatment.

Pre-existing antibodies that cross-react with idarucizumab were identified in approximately 12% (33/283) of phase I volunteers and 3.8% (19/501) of patients. No effect on the pharmacokinetics or pharmacokinetics of idarucizumab, nor on hypersensitivity reactions, was observed.

Treatment-persistent anti-idarucizumab antibodies were reported with low concentrations in 4% (10/224) of phase I volunteers and 1.6% (8/501) of patients showing an effect. The immunogenicity of idarucizumab is low. In a subgroup of 6 phase I volunteers, idarucizumab was given a second time, 2 months after the first dose. No antibodies to idarucizumab were detected in these subjects prior to the second administration. The ability to form antibodies against idarucizumab during treatment was detected in 1 person after a second dose of the drug. Nine patients resumed idarucizumab, all nine of which were reintroduced within 6 days of the first dose of idarucizumab. None of the patients re-administered with idarucizumab tested positive for anti-idarucizumab antibodies.

Preclinical pharmacodynamics

The porcine injury model was performed using a blunt object that caused liver injury after dabigatran was administered at doses that were above therapeutic concentrations, approximately 10 times higher than those in human plasma. Idarucizumab effectively and quickly neutralizes life-threatening bleeding within 15 minutes of injection. All pigs were rescued with doses of idarucizumab between 2.5 and 5 g. Without idarucizumab, the mortality rate in the anticoagulation group was 100%.

Preclinical studies with idarucizumab showed no interactions with

Drugs that increase circulating volume.

Coagulation factor concentrates such as prothrombin complexes (PCCs, such as factors 3 and 4), activated prothrombin complexes (aPCCs) and recombinant factor VIIa.

Other anticoagulants (eg, thrombin inhibitors other than dabigatran, factor Xa inhibitors including low molecular weight heparin, vitamin K antagonists, heparin). Thus, idarucizumab does not reverse the effects of other anticoagulants.

Pharmacokinetics

The pharmacokinetics of idarucizumab were studied in healthy volunteers aged 45 to 64 years who received a dose of 5 g intravenously.

Distribution

Idarucizumab shows a polyphasic pharmacokinetic pattern and limited extravascular distribution. Following an intravenous infusion of 5 g, the mean apparent volume of distribution at steady state (Vss) was 8.9 L (coefficient of apparent variation (gCV) 24.8%). During the elimination phase, the volume of distribution (Vz) was 41.8 L (coefficient of apparent variation 22.3%).

Biotransformation

The metabolism of antibodies can follow a number of different pathways. All of these pathways are involved in the biodegradation of antibodies into smaller molecules such as small peptides or amino acids, which are then reabsorbed and incorporated in protein synthesis. general.

Elimination

Idarucizumab is rapidly eliminated with a total clearance of 47.0 mL/min (apparent coefficient of variation 18.4%) and an initial half-life of 47 minutes (apparent coefficient of variation 11. 4%) and a terminal half-life of 10.3 hours (coefficient of apparent variation 18.9%). Following an intravenous infusion of 5 g idarucizumab, 32.1% (coefficient of apparent variation 60.0%) of the dose was recovered in the urine during the 6-hour sampling period and less than 1% in the following 18 hours. The remainder of the dose is assumed to be eliminated by protein catabolism, mainly by the kidneys.

After treatment with idarucizumab, proteinuria was observed. Transient proteinuria is a physiological response to renal protein spillage following a rapid infusion of 5 g of idarucizumab. Peak concentrations of transient proteinuria are achieved approximately 4 hours after administration of idarucizumab and return to normal within 12-24 hours. In some isolated cases, transient proteinuria persisted for more than 24 hours.

Patients with impaired renal function

In phase I clinical studies, Praxbind was studied in subjects with creatinine clearance ranging from 44 to 213 mL/min. Has not been studied in phase I in subjects with creatinine clearance less than 44 mL/min.

Depending on the degree of renal impairment, total clearance is reduced compared with healthy subjects, leading to increased circulating concentrations of idarucizumab.

Based on pharmacokinetic data from 347 patients with varying degrees of renal function (mean creatinine clearance 21-99 mL/min), an estimated increase in idarucizumab exposure (AUC0-24h) is estimated to be approximately 38% in patients with mild renal impairment (CrCL 50 - < 80 mL/min), about 90% in patients with moderate renal impairment (30 - < 50 mL/min) and about 146% in patients with severe renal impairment (CrCL 0 - < 30 mL/min). Since dabigatran is eliminated primarily by the kidneys, increased plasma concentrations of dabigatran have been observed with worsening renal function.

Based on the data and the extent of anticoagulation with dabigatran in patients, the anticoagulant effect of idarucizumab was not affected by impaired renal function.

Patients with impaired liver function

No effect of hepatic impairment, as assessed by liver injury as determined by elevated liver function test results, was observed on the pharmacokinetics of idarucizumab.

idarucizumab was studied in 58 patients with varying degrees of hepatic impairment. Compared with 272 patients without hepatic impairment, the median AUC of idarucizumab changed by -6%, 37%, and 10% in patients with AST/ALT increases of 1 to 2 times ULN, respectively (N=34). , 2 to 3 times ULN (N=3) and >3 times ULN (N=21). Based on pharmacokinetic data from 12 patients with liver disease, the AUC value of idarucizumab was increased by 10% compared with patients without liver disease.

Elderly/Gender/Race

Based on population pharmacokinetic analyses, gender, age, and race had no clinically relevant effects on the pharmacokinetics of idarucizumab.

Indications and uses

Praxbind is a specific anticoagulant of dabigatran and is indicated for patients treated with Pradaxa (dabigatran) when rapid reversal of the anticoagulant effect of dabigatran is required:

In case of emergency surgery/emergency procedure

In case of life-threatening or uncontrolled bleeding.

Dosage and Administration

The recommended dose of Praxbind is 5 g. Two 50 mL vials (2 x 2.5 g/50 mL).

Praxbind (2 x 2.5 g/50 mL) is administered intravenously, as two continuous infusions over a period of 5 to 10 minutes for each infusion or rapid intravenous injection.

In a small number of patients, reappearance of unbound free dabigatran plasma concentrations and concurrent prolongation of coagulation tests may occur up to 24 hours after administration of idarucizumab.

A second dose of 5 g Praxbind may be considered in the following situations:

Clinical recurrence of bleeding associated with prolonged clotting time, or

Patients who require a second emergency surgery/urgent procedure and have a prolonged clotting time.

The relevant coagulation parameters are the activated partial thromboplastin time (aPTT), the dilution thrombin time (dTT) or the ecarin clotting time (ECT).

Re-treatment with antithrombotic drugs

Pradaxa therapy can be restarted 24 hours after Praxbind administration if the patient's clinical condition is stable and the patient is well hemostasis.

Following Praxbind, treatment with other antithrombotic agents (such as low molecular weight heparin) may be initiated at any time if the patient's clinical condition is stable and the patient is well hemostasis.

Lack of anticoagulation therapy exposes patients to an increased risk of thrombosis caused by comorbidities or conditions.

Patients with impaired renal function

No dose adjustment is required in patients with renal impairment. Renal impairment did not affect the mediated effect of idarucizumab.

Patients with impaired liver function

No dose adjustment is required in patients with hepatic impairment.

Elderly patient

No dose adjustment is required in elderly patients 65 years of age and older.

Pediatric patient

The efficacy and safety of Praxbind in children under 18 years of age have not been established. No relevant data is available.

Instructions for use and operation

Before using parenteral medicinal products, they should be visually inspected for the presence of foreign substances and discoloration.

Praxbind must not be mixed with other drugs. An existing intravenous line can be used for the infusion of Praxbind. The infusion line should be rinsed with sterile 9 mg/mL (0.9%) sodium chloride solution before and after stopping the infusion. It should not be infused at the same time with other drugs in the same intravenous line.

Before use, the unopened vial can be kept at room temperature (below 30°C) for 48 hours if stored in its original container protected from light. When the solution was withdrawn from the vial, chemical and physical stability for use of idarucizumab was demonstrated for 6 h at room temperature. The solution should not be exposed to light for more than 6 hours.

Praxbind is available in single-dose only and contains no preservatives.

No incompatibilities between Praxbind and polyvinyl chloride, polyethylene or polyurethane infusion sets, or polypropylene syringes have been observed.

Warning

Idarucizumab binds specifically to dabigatran and counteracts the anticoagulant effect of dabigatran. The drug does not reverse the effect of other anticoagulants.

Praxbind treatment may be used in combination with medically appropriate standard supportive measures.

Hypersensitivity

The risks of using Praxbind in patients with hypersensitivity (e.g. anaphylaxis) to idarucizumab or any of the excipients should be weighed against the benefits of the drug in the event of emergency treatment. If an anaphylactic or other serious allergic reaction occurs, Praxbind should be discontinued immediately and appropriate treatment instituted.

Hereditary fructose intolerance

The recommended dose of Praxbind contains 4 g of sorbitol as an excipient. In patients with hereditary intolerance to fructose, parenteral administration of sorbitol has been associated with reports of hypoglycemia, hypophosphatemia, metabolic acidosis, hyperuricemia, acute liver failure with impaired excretory function. and aggregate, death. Therefore, in patients with hereditary fructose intolerance, the risks of treatment with Praxbind should be weighed against its effectiveness in the emergency setting. Where Praxbind is used in these patients, additional medical attention is required upon exposure to Praxbind and within 24 hours of exposure.

Thromboembolic events

Patients being treated with dabigatran are those with pre-existing medical conditions predisposing to thromboembolic events. Reversing the therapeutic effects of dabigatran puts patients at risk for thrombosis caused by underlying medical conditions. To reduce this risk, re-treatment with anticoagulants should be considered as soon as possible when medically appropriate.

Proteinuria test

Praxbind induces transient proteinuria as a physiological response to renal protein spillage following single/short-dose intravenous administration of idarucizumab. Transient proteinuria is not an indicator of kidney damage and should be considered during urinalysis.

Sodium composition

This medication contains 2.2 mmol (or 50 mg) of sodium in a single dose. Patients taking the drug should consider controlling their sodium intake.

Overdose

There is no clinical experience with Praxbind Overdosage.

The highest dose of Praxbind studied in healthy volunteers was 8 g. No safety signals have been identified in this target group.

Contraindications

None.

Use in pregnant and lactating women

Pregnant

There are no data on the use of Praxbind in pregnant women. Reproductive and developmental toxicity studies have not been performed due to nature and intended clinical use of the drug. Praxbind can be used during pregnancy if the benefits outweigh the risks.

Breastfeeding Women

It is not known whether idarucizumab is excreted in human milk.

Fertility

There are no data on the effects of Praxbind on fertility.

Interactive

Formal interaction studies between Praxbind and other medicinal products have not been performed. Based on the pharmacokinetic properties and highly specific binding to dabigatran, clinically relevant interactions with other drugs are considered unlikely.

Preclinical studies have shown no interaction with volume-expanding agents, clotting factor concentrates, and other anticoagulants other than dabigatran.

Incompatibility

This medicine must not be mixed with other medicines.

Side effects

In a phase III trial, the safety of Praxbind was evaluated in 503 patients who had uncontrolled bleeding or required emergency surgery or emergency procedure and were being treated with Pradaxa, as well as in 224 healthy volunteers in phase I trials.

No adverse reactions were noted.

Preservation

Store in the refrigerator (2oC-8oC).

No freezing. Store in original packaging, protected from light.

Presentation and packaging

Solution for injection/infusion: box of 2 bottles of 50mL.