The absolute bioavailability of ELIQUIS is approximately 50% for doses up to 10 mg.
ELIQUIS demonstrates linear pharmacokinetics with dose proportional increases in exposure for oral doses up to 10 mg.
At doses ≥25 mg, ELIQUIS displays dissolution-limited absorption with decreased bioavailability.
ELIQUIS exposure parameters exhibit low to moderate variability reflected by a within-subject and inter-subject variability of ~20% CV and ~30% CV, respectively.
Further information on the absorption of ELIQUIS is available in the SmPC.
Plasma protein binding in humans is approximately 87%. The volume of distribution (Vss) is approximately 21 litres.
O-demethylation and hydroxylation at the 3-oxopiperidinyl moiety are the major sites of biotransformation. ELIQUIS is metabolised mainly via CYP3A4/5, with minor contributions from CYP1A2, 2C8, 2C9, 2C19, and 2J2.
Unchanged ELIQUIS is the major drug-related component in human plasma, with no active circulating metabolites present.
ELIQUIS is a substrate of transport proteins, P-gp and breast cancer resistance protein (BCRP).
ELIQUIS has multiple routes of elimination.
Of the administered ELIQUIS dose in humans, approximately 25% was recovered as metabolites, with the majority recovered in faeces.
Additional contributions from biliary and direct intestinal excretion were observed in clinical and nonclinical studies, respectively.
ELIQUIS has a total clearance of about 3.3 l/h and a half-life of approximately 12 hours.
Elderly patients (>65 years) exhibited higher plasma concentrations than younger patients, with mean AUC values being approximately 32% higher and no difference in Cmax.
Exposure to ELIQUIS was approximately 18% higher in females than in males.
Compared to ELIQUIS exposure in subjects with body weight of 65–85 kg, body weight >120 kg was associated with approximately 30% lower exposure and body weight <50 kg was associated with approximately 30% higher exposure.
The results across phase I studies showed no discernible difference in ELIQUIS pharmacokinetics between White / Caucasian, Asian and Black / African American subjects. Findings from a population pharmacokinetic analysis in patients who received ELIQUIS were generally consistent with the Phase I results.
There was no impact of impaired renal function on peak concentration of ELIQUIS. There was an increase in ELIQUIS 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, ELIQUIS 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 ELIQUIS plasma concentration and anti-FXa activity.
In subjects with end-stage renal disease (ESRD), the AUC of ELIQUIS was increased by 36% when a single dose of ELIQUIS 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 ELIQUIS 5 mg, decreased ELIQUIS AUC by 14% in these ESRD subjects, corresponding to an ELIQUIS dialysis clearance of 18 ml/min. Therefore, haemodialysis is unlikely to be an effective means of managing ELIQUIS overdose.
In a study comparing eight 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 ELIQUIS 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.