Apixaban

Apixaban is a potent, oral, reversible, direct and highly selective active site inhibitor of factor Xa. It does not require antithrombin III for antithrombotic activity. Apixaban inhibits free and clot-bound factor Xa, and prothrombinase activity. Apixaban has no direct effects on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin. By inhibiting factor Xa, apixaban prevents thrombin generation and thrombus development. Preclinical studies of apixaban in animal models have demonstrated antithrombotic efficacy in the prevention of arterial and venous thrombosis at doses that preserved haemostasis.

The pharmacodynamic effects of apixaban are reflective of the mechanism of action (FXa inhibition). As a result of FXa inhibition, apixaban prolongs clotting tests such as prothrombin time (PT), INR and activated partial thromboplastin time (aPTT). In adults, changes observed in these clotting tests at the expected therapeutic dose are small and subject to a high degree of variability. They are not recommended to assess the pharmacodynamic effects of apixaban. In the thrombin generation assay, apixaban reduced endogenous thrombin potential, a measure of thrombin generation in human plasma.

Apixaban also demonstrates anti-Factor Xa activity as evident by reduction in Factor Xa enzyme activity in multiple commercial anti-Factor Xa kits, however results differ across kits. Data from adult clinical studies are only available for the Rotachrom Heparin chromogenic assay. Anti-Factor Xa activity exhibits a close direct linear relationship with apixaban plasma concentration, reaching maximum values at the time of apixaban peak plasma concentrations. The relationship between apixaban plasma concentration and anti-Factor Xa activity is approximately linear over a wide dose range of apixaban. Results from apixaban paediatric studies indicate that the linear relationship between apixaban concentration and AXA is consistent with the previously documented relationship in adults. This lends support to the documented mechanism of action of apixaban as a selective inhibitor of FXa.

Absorption

In adults, the absolute bioavailability of apixaban is approximately 50% for doses up to 10 mg. Apixaban is rapidly absorbed with maximum concentrations (C_max) appearing 3 to 4 hours after tablet intake. Intake with food does not affect apixaban AUC or C_max at the 10 mg dose. Apixaban can be taken with or without food.

Apixaban demonstrates linear pharmacokinetics with dose proportional increases in exposure for oral doses up to 10 mg. At doses ≥25 mg apixaban displays dissolution limited absorption with decreased bioavailability. Apixaban exposure parameters exhibit low to moderate variability reflected by a within-subject and inter-subject variability of ~20% CV and ~30% CV, respectively.

Following oral administration of 10 mg of apixaban as 2 crushed 5 mg tablets suspended in 30 mL of water, exposure was comparable to exposure after oral administration of 2 whole 5 mg tablets. Following oral administration of 10 mg of apixaban as 2 crushed 5 mg tablets with 30 g of apple puree, the C_max and AUC were 21% and 16% lower, respectively, when compared to administration of 2 whole 5 mg tablets. The reduction in exposure is not considered clinically relevant.

Following administration of a crushed 5 mg apixaban tablet suspended in 60 mL of G5W and delivered via a nasogastric tube, exposure was similar to exposure seen in other clinical studies involving healthy subjects receiving a single oral 5 mg apixaban tablet dose.

Given the predictable, dose-proportional pharmacokinetic profile of apixaban, the bioavailability results from the conducted studies are applicable to lower apixaban doses.

Paediatric population

Apixaban is rapidly absorbed, reaching maximum concentration (C_max) approximately 2 hours after single-dose administration.

Distribution

In adults, plasma protein binding is approximately 87%. The volume of distribution (V_ss) is approximately 21 litres.

Biotransformation and elimination

Apixaban has multiple routes of elimination. Of the administered apixaban dose in adults, approximately 25% was recovered as metabolites, with the majority recovered in faeces. In adults, renal excretion of apixaban accounted for approximately 27% of total clearance. Additional contributions from biliary and direct intestinal excretion were observed in clinical and nonclinical studies, respectively.

In adults, apixaban has a total clearance of about 3.3 L/h and a half-life of approximately 12 hours.

In paediatrics, apixaban has a total apparent clearance of about 3.0 L/h.

O-demethylation and hydroxylation at the 3-oxopiperidinyl moiety are the major sites of biotransformation. Apixaban is metabolised mainly via CYP3A4/5 with minor contributions from CYP1A2, 2C8, 2C9, 2C19, and 2J2. Unchanged apixaban is the major active substance-related component in human plasma with no active circulating metabolites present. Apixaban is a substrate of transport proteins, P-gp and breast cancer resistance protein (BCRP).

No data on apixaban plasma protein binding specific to paediatric population is available.

Elderly

Elderly patients (above 65 years) exhibited higher plasma concentrations than younger patients, with mean AUC values being approximately 32% higher and no difference in C_max.

Renal impairment

There was no impact of impaired renal function on peak concentration of apixaban. There was an increase in apixaban exposure correlated to decrease in renal function, as assessed via measured creatinine clearance. In individuals with mild (creatinine clearance 51-80 mL/min), moderate (creatinine clearance 30-50 mL/min) and severe (creatinine clearance 15-29 mL/min) renal impairment, apixaban plasma concentrations (AUC) were increased 16, 29, and 44% respectively, compared to individuals with normal creatinine clearance. Renal impairment had no evident effect on the relationship between apixaban plasma concentration and anti-Factor Xa activity.

In subjects with end-stage renal disease (ESRD), the AUC of apixaban was increased by 36% when a single dose of apixaban 5 mg was administered immediately after haemodialysis, compared to that seen in subjects with normal renal function. Haemodialysis, started two hours after administration of a single dose of apixaban 5 mg, decreased apixaban AUC by 14% in these ESRD subjects, corresponding to an apixaban dialysis clearance of 18 mL/min. Therefore, haemodialysis is unlikely to be an effective means of managing apixaban overdose.

In paediatric patients ≥2 years of age, severe renal impairment is defined as an estimated glomerular filtration rate (eGFR) less than 30 mL/min/1.73 m² body surface area (BSA). In Study CV185325, in patients less than 2 years of age, the thresholds defining severe renal impairment by sex and post-natal age are summarized in the table below; each corresponds to an eGFR <30 mL/min/1.73 m² BSA for patients ≥2 years of age.

eGFR eligibility thresholds for study CV185325:

|<>_.Postnatal age (gender) |<>_.GFR reference range
(mL/min/1.73 m²) |<>_.Eligibility threshold for
eGFR* |

^* Eligibility threshold for CV185325 study participation, where estimated glomerular filtration rate (eGFR) was calculated per the updated bedside Schwartz equation (Schwartz, GJ et al., CJASN 2009). This per protocol threshold corresponded to the eGFR below which a prospective patient was considered to have “inadequate renal function” that precluded participation in Study CV185325. Each threshold was defined as an eGFR <30% of 1 standard deviation (SD) below the GFR reference range for age and gender. Threshold values for patients <2 years of age correspond to an eGFR <30 mL/min/1.73 m², the conventional definition of severe renal failure in patients >2 years of age.

Paediatric patients with glomerular filtration rates ≤55 mL/min/1.73 m² did not participate in Study CV185325, although those with mild to moderate levels of renal impairment (eGFR ≥30 to <60 mL/min/1.73 m² BSA) were eligible. Based on adult data and limited data in all apixaban-treated paediatric patients, no dose adjustment is necessary in paediatric patients with mild to moderate renal impairment. Apixaban is not recommended in paediatric patients with severe renal impairment.

Hepatic impairment

In a study comparing 8 subjects with mild hepatic impairment, Child-Pugh A score 5 (n=6) and score 6 (n=2), and 8 subjects with moderate hepatic impairment, Child-Pugh B score 7 (n=6) and score 8 (n=2), to 16 healthy control subjects, the single-dose pharmacokinetics and pharmacodynamics of apixaban 5 mg were not altered in subjects with hepatic impairment. Changes in anti-Factor Xa activity and INR were comparable between subjects with mild to moderate hepatic impairment and healthy subjects.

Apixaban has not been studied in paediatric patients with hepatic impairment.

Gender

Exposure to apixaban was approximately 18% higher in females than in males. Gender differences in pharmacokinetic properties were not studied in paediatric patients.

Ethnic origin and race

The results across phase I studies showed no discernible difference in apixaban pharmacokinetics between White/Caucasian, Asian and Black/African American subjects. Findings from a population pharmacokinetic analysis in patients who received apixaban were generally consistent with the phase I results.

Differences in pharmacokinetic properties relating to ethnic origin and race were not studied in paediatric patients.

Body weight

Compared to apixaban exposure in subjects with body weight of 65 to 85 kg, body weight >120 kg was associated with approximately 30% lower exposure and body weight <50 kg was associated with approximately 30% higher exposure.

Administration of apixaban to paediatric patients is based on a fixed-dose by weight-tier regimen.

Pharmacokinetic/pharmacodynamic relationship

In adults, the pharmacokinetic/pharmacodynamic (PK/PD) relationship between apixaban plasma concentration and several PD endpoints (anti-Factor Xa activity [AXA], INR, PT, aPTT) has been evaluated after administration of a wide range of doses (0.5–50 mg). The relationship between apixaban plasma concentration and anti-Factor Xa activity was best described by a linear model. The PK/PD relationship observed in patients was consistent with that established in healthy subjects.

Similarly, results from apixaban paediatric PK/PD assessment indicate a linear relationship between apixaban concentration and AXA. This is consistent with the previously documented relationship in adults.

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, fertility and embryo-foetal development and juvenile toxicity.

The major observed effects in the repeated dose toxicity studies were those related to the pharmacodynamic action of apixaban on blood coagulation parameters. In the toxicity studies little to no increase of bleeding tendency was found. However, since this may be due to a lower sensitivity of the non-clinical species compared to humans, this result should be interpreted with caution when extrapolating to humans.

In rat milk, a high milk to maternal plasma ratio (C_max about 8, AUC about 30) was found, possibly due to active transport into the milk.