gh-fat, respectively. The effect of food on betrixaban PK could be observed for up to 6 hours after meal intake.
Distribution
The apparent volume of distribution is 32 L/kg. In vitro plasma protein binding is 60%.
Elimination
The effective half-life of betrixaban is 19 to 27 hours.
Metabolism
Unchanged betrixaban is the predominant component found in human plasma. Two inactive major metabolites formed by CYP-independent hydrolysis comprise the other components in plasma, accounting for 15 to 18% of the circulating drug-related material. Less than 1% of the minor metabolites could be formed via metabolism by the following CYP enzymes; 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, and 3A4.
Excretion
Following oral administration of radio-labeled betrixaban approximately 85% of the administered compound was recovered in the feces and 11% recovered in the urine. In a study of intravenous betrixaban a median value of 17.8% of the absorbed dose was observed as unchanged betrixaban in urine.
Specific Populations
Male and Female Patients
No clinically significant changes in betrixaban pharmacokinetics were observed between males and females.
Patients with Renal Impairment
In a dedicated renal impairment study mean AUC0-24 on day 8 was increased by 1.89, 2.27 and 2.63-fold in mild (eGFRMDRD ≥ 60 to < 90 mL/min/1.73 m2), moderate (eGFRMDRD ≥ 30 to < 60 mL/min/1.73 m2) and severe (eGFRMDRD ≥ 15 to < 30 mL/min/1.73 m2) renal impaired patients respectively compared to healthy volunteers [see USE IN SPECIFIC POPULATIONS (8.6)].
Patients with Hepatic Impairment
Studies with betrixaban in patients with hepatic impairment have not been conducted and the impact of hepatic impairment on the exposure to betrixaban has not been eva luated [see USE IN SPECIFIC POPULATIONS (8.7)].
Drug Interaction Studies
The effects of coadministered drugs on the pharmacokinetics of betrixaban exposure based on drug interaction studies are summarized in Figure 1.
Figure 1: Effect of Coadministered Drugs on the Pharmacokinetics of Betrixaban
Figure 1
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies with betrixaban have not been performed.
Betrixaban was not mutagenic in bacteria (Ames-Test) or clastogenic in Chinese hamster ovary cells in vitro or in the rat micronucleus test in vivo.
In a study to assess fertility and early embryonic development to implantation, oral doses of betrixaban were administered to male and female rats. There was no evidence that betrixaban up to 150 mg/kg/day adversely affected male or female fertility, reproductive performance, or embryo-fetal viability.
14 CLINICAL STUDIES
The clinical evidence for the effectiveness of BEVYXXA is derived from the APEX clinical trial [NCT01583218]. APEX was a randomized, double-blind, multinational study comparing extended duration BEVYXXA (35 to 42 days) to short duration of enoxaparin (6 to 14 days) in the prevention of venous thromboembolic events (VTE) in an acutely medically ill hospitalized population with risk factors for VTE.
Eligible patients included adults who were at least 40 years of age, hospitalized for an acute medical illness, at risk for VTE due to moderate or severe immobility, and had additional risk factors for VTE (described below). Expected duration of hospitalization was at least 3 days and patients were expected to be moderately or severely immobilized for at least 24 hours. The causes for hospitali |
