What Is Apixaban?

The chemical name of apixaban is 1- (4-methoxyphenyl) -7-oxo-6 [4- (2-oxopiperidin-1-yl) phenyl] -4,5 , 6,7-tetrahydro-1 H -pyrazole [3,4-c] pyridine-3-carboxamide, the molecular formula is C ₂₅ H ₂₅ N ₅ O ₄ , the molecular weight is 459.49700, and the density is 1.42g / cm ³ , The boiling point is 770.468ºC at 760 mmHg, the flash point is 419.764ºC, and the refractive index is 1.705. Adult patients clinically used for elective hip or knee replacement to prevent venous thromboembolic events (VTE).

The chemical name of apixaban is 1- (4-methoxyphenyl) -7-oxo-6 [4- (2-oxopiperidin-1-yl) phenyl] -4,5 , 6,7-tetrahydro-1 H -pyrazole [3,4-c] pyridine-3-carboxamide, the molecular formula is C ₂₅ H ₂₅ N ₅ O ₄ , the molecular weight is 459.49700, and the density is 1.42g / cm ³ , The boiling point is 770.468ºC at 760 mmHg, the flash point is 419.764ºC, and the refractive index is 1.705. Adult patients clinically used for elective hip or knee replacement to prevent venous thromboembolic events (VTE).

Chinese name

Apixaban

Foreign name

apixaban

CAS number

503612-47-3

Molecular formula

C25H25N5O4

Molecular weight

459.49700

Introduction of Apixaban Compound

Apixaban Basic Information

Chinese name

Chinese alias: Damamod; 4,5,6,7-tetrahydro-1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxo-1-piper Pyridyl) phenyl] -1H-pyrazolo [3,4-c] pyridine-3-carboxamide; apixaban;

English name: apixaban

English alias: 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxopiperidin-1-yl) phenyl] -4,5-dihydropyrazolo [3,4-c] pyridine-3-carboxamide; UNII-3Z9Y7UWC1J; Apixaban; Eliquis;

CAS number: 503612-47-3

Molecular formula: C ₂₅ H ₂₅ N ₅ O ₄

Molecular weight: 459.49700

Structural formula:

Exact mass: 459.19100

PSA: 110.76000

LogP: 3.52990 ^[1]

Apixaban physical and chemical properties

Density: 1.42g / cm ³

Boiling point: 770.468ºC at 760 mmHg

Flash point: 419.764ºC

Refractive index: 1.705 ^[1]

Apixaban uses

The drug is used to prevent venous thromboembolism (vte) events in adult patients undergoing elective hip or knee arthroplasty. ^[1]

About Apixaban

In 2007, Bristol-Myers Squibb and Pfizer formally implemented a global strategic cooperation agreement to jointly develop and sell the anticoagulant product apixaban; in 2011, in the 27 European Union countries and Iceland and Norway, it was the first to approve the use of elective hip Prevention of venous thrombosis in adult patients undergoing knee replacement surgery; In January 2013, the import drug license issued by the State Food and Drug Administration of China was used in adult patients for elective replacement of hip or knee joints to prevent venous thromboembolism Incident (VTE), and then officially listed in China in April 2013.

Apixaban is a new type of oral anticoagulant drug, a new type of oral factor Xa inhibitor, and a drug used to prevent and treat thrombosis.

The recommended dose is 2.5 mg, taken orally twice a day, which effectively prevents venous thromboembolism without increasing the risk of bleeding, and does not require routine monitoring of coagulation function and dose adjustment.

Apixaban instruction manual

The main ingredient of this product is apixaban.

Chemical composition: 1- (4-methoxyphenyl) -7-oxo-6 [4- (2-oxopiperidin-1-yl) phenyl] -4,5,6,7-tetrahydro -1H-pyrazole [3,4-c] pyridine-3-carboxamide

Chemical Structure:

Molecular formula: C ₂₅ H ₂₅ N ₅ O ₄

Molecular weight: 459.50 ^[2]

Apixaban traits

This product is a yellow film-coated tablet. After removing the coating, it is white to off-white ^[2]

Apixaban indications

Adult patients for elective hip or knee replacement to prevent venous thromboembolic events (VTE) ^[2]

Apixaban usage and dosage

The recommended dosage of this product is 2.5 mg each time, taken orally twice a day, taken with water, and not affected by meals. The first dose should be between 12 and 24 hours after surgery. When deciding what time to take within this time window, doctors need to consider both the potential benefits of early anticoagulation to prevent VTE and the risk of bleeding after surgery.

For patients undergoing hip arthroplasty: 32 to 38 days recommended

For patients undergoing knee arthroplasty: 10 to 14 days recommended

If a missed dose occurs, the patient should take this product immediately and then continue taking the drug twice daily. When converting from anticoagulant for injection to treatment with this product, it can be started from the next time of administration (or vice versa). See [Drug Interactions] ^[2]

Apixaban adverse reactions

The safety of apixaban was evaluated in a phase II clinical trial and three phase III clinical trials. A total of 5924 patients underwent major orthopedic surgery of the lower extremity (selective hip replacement or knee replacement) in these trials. , Taking 2.5 mg of apixaban three times a day for up to 38 days of treatment.

A total of 11% of patients receiving apixaban 2.5 mg twice daily experienced adverse reactions. As with other anticoagulant drugs, bleeding may only occur during the treatment of apixaban when there are related risk factors, such as damage to organs that are prone to bleeding. Common adverse reactions include anemia, bleeding, bruising and nausea. The side effects should be explained in conjunction with the surgical background.

Like other anticoagulant drugs, apixaban may cause an increased risk of recessive or overt bleeding in some tissues or organs, which may lead to anemia after bleeding. The signs, symptoms, and severity of bleeding will vary depending on the location, degree, or extent of the bleeding (see [Cautions] and [Clinical Trials]).

Adverse reactions during treatment of patients with elective hip or knee replacement ^[2]

Apixaban Taboo

Allergic to active ingredients or any excipients in tablets; clinically significant active bleeding; liver disease with coagulopathy and risk of clinically relevant bleeding (see [Pharmacokinetics]) ^[2]

Apixaban precautions

Bleeding risk

As with other anticoagulants, patients taking apixaban should be closely monitored for signs of bleeding. Apixaban should be used with caution in patients with the risk of bleeding: congenital or acquired bleeding disease; active gastrointestinal ulcer disease; bacterial endocarditis; thrombocytopenia; abnormal platelet function; hemorrhagic History of stroke; uncontrolled severe hypertension; recent brain, spinal or ophthalmic surgery. If severe bleeding occurs, apixaban should be discontinued (see [Overdose]).

Kidney damage

No dose adjustment is necessary for patients with mild or moderate renal impairment (see [Pharmacokinetics]).

Limited clinical data in patients with severe renal impairment (creatinine clearance of 15-29 ml / min) indicate that apixaban plasma levels are elevated in this patient population. Apixaban alone or in combination with acetyl Salicylic acid should be used with caution in these patients (see [Pharmacokinetics]).

Since no clinical data are available for patients with creatinine clearance <15ml / min or dialysis patients, these patients are not recommended to take apixaban (see [Pharmacokinetics]).

Elderly patients

The clinical experience of apixaban in combination with acetylsalicylic acid in elderly patients is limited. Because of the increased risk of bleeding, elderly patients should be cautious when taking these two drugs in combination.

Liver damage

Apixaban is contraindicated in patients with liver disease associated with abnormal blood coagulation and risk of clinically relevant bleeding (see [Contraindications]).

Apixaban is not recommended for patients with severe liver damage (see [Pharmacokinetics]).

For patients with mild and moderate liver damage (Child Pugh A or B), apixaban should be taken with caution (see [Pharmacokinetics]).

Patients with elevated ALT / AST> 2 * ULN or total bilirubin 1.5 * ULN have not been selected for clinical trials. Therefore, apixaban should be used with caution in these populations (see [Pharmacokinetics ). ALT should be routinely tested before surgery.

Hip fracture surgery

There are no clinical trials evaluating the effectiveness and safety of apixaban in patients undergoing hip fracture surgery. Therefore, these patients are not recommended to take apixaban.

Excipient information

This product contains lactose. Patients with rare hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this product.

Impact on the ability to drive and operate machinery

Apixaban has no or negligible effect on the ability to drive and operate machinery. ^[2]

Apixaban Pharmacology and Toxicology

It is an oral selective activation factor X inhibitor, which can prevent thrombosis, but the adverse effects of bleeding are lower than the old drug warfarin, and it is used for thrombosis prevention in patients who have undergone hip or knee replacement surgery. ^[2]

Apixaban for pregnant and lactating women

Pregnancy

Animal studies have not found this product to have direct or indirect reproductive toxicity. There is no data on the application of apixaban in pregnant women, and the application of apixaban is not recommended during pregnancy.

Lactating women

It is not clear whether apixaban or its metabolites enter human milk. Existing animal experimental data show that apixaban can enter breast milk. In rat milk, it was found that the milk-maternal plasma drug concentration ratio was high (Cmax was about 8 and AUC was about 30), probably because the drug was actively transported into the milk. The risks to newborns and infants cannot be ruled out.

It must be decided whether to stop breastfeeding or stop / avoid apixaban treatment. ^[2]

Apixaban for children

There are no data on the safety and effectiveness of using apixaban in patients under the age of 18. ^[2]

Apixaban medication for elderly patients

No need to adjust the dose ^[2]

Apixaban overdose

There is no antidote against apixaban. Excessive apixaban may increase the risk of bleeding. When bleeding complications occur, the drug should be discontinued immediately and the cause of the bleeding should be identified. Consideration should be given to appropriate treatment measures such as surgical hemostasis, fresh frozen plasma transfusion, etc.

In a controlled clinical trial, healthy volunteers take up to 50 mg of apixaban orally for 3 to 7 days (25 mg twice daily for 7 days or 50 mg once daily for 3 days) [equivalent to human daily 10 times the maximum recommended dose], no clinically significant adverse reactions occurred.

A preclinical trial with dogs found that oral activated carbon can reduce apixaban exposure within 3 hours after administration of apixaban; therefore, the use of activated carbon can be considered when dealing with apixaban excess.

If life-threatening bleeding cannot be controlled with the above treatments, the administration of recombinant factor VIIa may be considered. However, there is currently no experience with recombinant factor VIIa in patients taking apixaban. Consider repeated administration of recombinant factor VIIa, and adjust the dose according to the improvement of bleeding. ^[2]

Apixaban clinical trial

Apixaban clinical research project aims to demonstrate the effectiveness and safety of apixaban in preventing venous thromboembolism in adult patients undergoing elective hip or knee arthroplasty. A total of 8,464 patients were randomly assigned to two key double-blind, international multicenter trials comparing apixaban 2.5 mg twice daily (4236 patients) and enoxaparin 40 mg once daily (4228 patients). treatment plan. Among them, there were 1262 patients aged 75 years or older (618 patients in the apixaban group), 1004 patients with low body weight (60kg) (499 patients in the apixaban group), and 1495 patients with a BMI index 33kg / m (apixaban group) 743 patients) and 415 patients with moderate renal impairment (203 patients in the apixaban group).

In the ADVANCE-3 trial, a total of 5,407 patients underwent elective hip replacement surgery, and in the ADVANCE-2 trial, a total of 3,057 patients underwent elective knee replacement surgery. Subjects received 2.5 mg of apixaban orally twice daily or 40 mg of enoxaparin subcutaneously once daily. The first dose of apixaban was 12 to 24 hours after surgery, and enoxaparin was administered systemically from 9 to 15 hours before surgery. Both apixaban and enoxaparin were administered for 32 to 38 days in the ADVANCE-3 trial and 10 to 14 days in the ADVANCE-2 trial.

According to the medical history of patients in the ADVANCE-3 and ADVANCE-2 study population (8464 patients), 46% had hypertension, 10% had hyperlipidemia, 9% had diabetes, and 8% had coronary heart disease.

Compared with enoxaparin, apixaban significantly reduced the primary endpoint-the incidence of all VTE / all-cause death composite endpoints, and major VTE endpoint events-in patients undergoing elective hip replacement or knee replacement The incidence of composite endpoints of deep vein thrombosis (DVT), non-fatal pulmonary embolism (PE), and VTE-related deaths was statistically superior (see Table 2)

In patients taking apixaban 2.5 mg twice daily, compared with inoparin 40 mg once daily, the safety endpoint was a composite of major bleeding events, major bleeding and clinically significant non-major (CRNM) bleeding, and all bleeding events. The incidence is comparable (see Table 3). All bleeding criteria included surgical site bleeding.

In the ADVANCE-2 trial, a total of 180 patients from 6 research centers in China were randomly assigned to double-blind study medications (90 in each treatment group). In the ADVANCE-3 trial, a total of 245 patients from 7 research centers in China were randomly assigned to double-blind study medications (121 in the apixaban group; 124 in the enoxaparin group).

Among Chinese subjects, the overall effectiveness of apixaban was consistent with the overall results of the study. In the Chinese subgroup, fewer endpoint events were observed in the apixaban 2.5 mg BID treatment group than in the enoxaparin 40 mg QD treatment group (see Table 4).

Among Chinese subjects, the general safety characteristics of apixaban were consistent with those in global studies. Apixaban was the safest and well tolerated in Chinese subjects, with few bleeding events reported throughout the trial (see Table 5). In addition, the overall adverse event rate was lower in Chinese subjects, and no Chinese subjects died.

Total occurrence of adverse events such as bleeding, anemia, and transaminase abnormalities (such as alanine aminotransferase levels) in patients in the apixaban group in phase II and III studies conducted in patients undergoing elective hip and knee replacement surgery The rate is numerically lower than the enoxaparin group. In the knee replacement surgery study, PE occurred in 4 patients in the apixaban group during the intent treatment, and no PE occurred in the enoxaparin group for unknown reasons. In the Chinese subgroup study, no PE occurred in either group. ^[2]

Apixaban Pharmacology and Toxicology

Pharmacological action

Apixaban is a potent, orally effective, reversible, direct, and highly selective factor Xa active site inhibitor. Its antithrombotic activity is independent of antithrombin III. Apixaban inhibits free and thrombogenic factor Xa and inhibits prothrombin activity. Apixaban has no direct effect on platelet aggregation, but indirectly inhibits thrombin-induced platelet aggregation. By inhibiting factor Xa, apixaban inhibits thrombin production and inhibits thrombosis. The results of preclinical tests in animal models show that apixaban has antithrombotic effects at dose levels that do not affect hemostatic function and can prevent arterial and venous thrombosis.

Toxicology research

Genetic toxicity: Amesaban Ames test, Chinese hamster ovary cell chromosome aberration test, rat bone marrow micronucleus test results were all negative.

Reproductive toxicity: Rat fertility and early embryonic developmental toxicity test results showed that apixaban was administered at a dose of 600 mg / kg, and maternal toxicity showed an effect on coagulation parameter values, and no significant effect on maternal fertility was seen. Significant effects on the growth and development of the offspring; pregnant rats and pregnant rabbits were administered orally with apixabanda 3000mg / kg / day and 1500mg / kg / day, respectively, and no significant abnormalities in the growth and development of drug-related offspring were seen; Perinatal reproductive toxicity test results in rats showed that the NOAEL effect on maternal reproductive function was 1000 mg / kg / day, and the NOAEL effect on offspring growth and development was not 25 mg / kg / day.

Carcinogenicity: Mice and rats were orally administered apixaban for a 104-week carcinogenicity test. Male and female mice received doses of 1500 mg / kg / day and 3000 mg / kg / day, respectively. The incidence of tumors increased. Rats were administered orally with apixaban at a dose of 600 mg / kg / day, and there was no increase in the incidence of drug-related tumors. ^[2]

Apixaban Pharmacokinetics

absorb

Within the 10 mg dose range, the absolute bioavailability of apixaban is approximately 50%. Apixaban is absorbed quickly and reaches the maximum concentration (Cmax) 3 to 4 hours after taking it. Food intake has no effect on AUC or Cmax of 10 mg of apixaban. Apixaban can be taken with or without meals.

In the 10 mg dose range, apixaban has a linear pharmacokinetic profile and is dose-dependent. When the dose of apixaban was 25mg, it showed dissolution-restricted absorption and the bioavailability decreased. The exposure parameters of apixaban show low to moderate variability, with an intra-individual coefficient of variation (CV) of approximately 20% and inter-individual approximately 30%.

distributed

In humans, the binding rate to plasma proteins is about 87%. The distribution volume (Vss) is approximately 21 liters.

metabolism

The main site of apixaban biotransformation is o-demethylation or hydroxylation of a 3-piperidone group. Apixaban is mainly metabolized by CYP3A4 / 5, and rarely is metabolized by CYP1A2, 2C8, 2C9, 2C19, and 2J2. Prototype apixaban is the main drug-related component in human plasma, and no active circulating metabolites have been found. Apixaban is a substrate for the transporter P-gp and breast cancer resistance protein (BCRP).

excretion

Apixaban can be cleared in a number of ways. After human administration of apixaban, about 25% appeared as metabolite formation, and the vast majority were detected in feces. Kidney excretion accounts for approximately 27% of total clearance. In addition, clinical trials have found additional bile excretion and non-clinical trials have found additional direct intestinal excretion. The total clearance of apixaban is about 3.3L / h, and the half-life is about less than 12 hours.

Apixaban special population

Kidney damage

Renal damage has no effect on the maximum plasma concentration of apixaban. Apixaban exposure increased with decreasing renal function (as assessed by creatinine clearance). Compared with those with normal clearance of creatinine, mild renal damage (creatinine clearance 51-80ml / mim), moderate damage (creatinine clearance 30-50ml / mim), and severe damage (creatinine clearance 15-29ml / mim) The area under the plasma concentration curve (AUC) of apixaban in patients increased by 16%, 29%, and 44%, respectively. Renal damage has no significant effect on the relationship between apixaban plasma concentration and anti-FXa activity.

Liver damage

In a comparison of mild liver damage (Child Pugh A grade, with a score of 5 and 6 cases, and a score of 6 points and 2 cases) and moderate liver damage (Child Pugh B, with a score of 7 and 6 cases, and a score of 8 and 2 cases) ) And healthy subjects (16 cases), after the word administration of apixaban 5mg, there was no change in the pharmacokinetics and pharmacodynamics of apixaban in patients with liver damage. Changes in FXa activity and INR were comparable to healthy subjects.

Elderly patients

Elderly patients (greater than 65 years) have higher plasma concentrations than younger patients, with an average AUC increase of approximately 32%.

gender

Apixaban exposure is approximately 18% higher in women than in men, and no dose adjustment is required.

Race and race

The results of the Phase I clinical trial showed no significant differences in the pharmacokinetics of apixaban between white / Caucasian, Asian, and black / African American. Population pharmacokinetic analysis was performed on patients receiving apixaban after elective hip or knee joint replacement, and the results were consistent with the conclusions of the phase I trial described above.

body weight

Compared with patients weighing 65kg to 85kg, exposure to apixaban was reduced by approximately 30% in patients weighing> 120kg, and exposure was increased by approximately 30% in patients weighing <50kg. No dose adjustment was required.

Pharmacokinetic / pharmacodynamic relationship

The pharmacokinetic / pharmacodynamic (PK / PD) relationship between apixaban blood concentration and several pharmacodynamic endpoints (anti-Xa factor activity, INR, PT, aPTT) has been evaluated. The dosage of pisarban ranges from 0.5 mg to 50 mg. The relationship between apixaban concentration and factor Xa activity best fits the linear model. The PK / PD relationship in patients undergoing elective hip or knee arthroplasty was consistent with the results in healthy subjects.

Apixaban storage

Store below 30

Apixaban packaging

Alu-PVC / PVDC blister pack, boxed, 10 pieces / box, 14 pieces / box, 20 pieces / box, 60 pieces / box.

Apixaban validity period

36 months

Apixaban implementation standards

Import drug registration standard JX20120076

Apixaban approval number

Import drug registration certificate number: H20130063; H20130075

Apixaban manufacturer

Bristol-Myers Squibb Manufacturing Company. ^[2]