Evaluation of safety, pharmacokinetics, and pharmacodynamics of apixaban in pediatric subjects at risk of venous or arterial thrombotic disorder

Abstract

Apixaban is an oral small-molecule, direct factor Xa (FXa) inhibitor approved in adults for treatment of deep vein thrombosis and pulmonary embolism, and for reducing risk of venous thromboembolism recurrence after initial anticoagulant therapy. This phase I study (NCT01707394) evaluated the pharmacokinetics (PKs), pharmacodynamics (PDs), and safety of apixaban in pediatric subjects (<18 years), enrolled by age group, at risk of venous or arterial thrombotic disorder. A single apixaban dose, targeting adult steady-state exposure with apixaban 2.5 mg, was administered using two pediatric formulations: 0.1 mg sprinkle capsule (age <28 days); 0.4 mg/ml solution (age 28 days to <18 years; dose range, 1.08-2.19 mg/m² ). End points included safety, PKs, and anti-FXa activity. For PKs/PDs, four to six blood samples were collected ≤26 h postdosing. A population PK model was developed with data from adults and pediatric subjects. Apparent oral clearance (CL/F) included fixed maturation function based on published data. From January 2013 to June 2019, 49 pediatric subjects received apixaban. Most adverse events were mild/moderate, and the most common was pyrexia (n = 4/15). Apixaban CL/F and apparent central volume of distribution increased less than proportionally with body weight. Apixaban CL/F increased with age, reaching adult values in subjects aged 12 to <18 years. Maturation affected CL/F most notably in subjects aged <9 months. Plasma anti-FXa activity values were linearly related to apixaban concentrations, with no apparent age-related differences. Pediatric subjects tolerated single apixaban doses well. Study data and population PK model supported phase II/III pediatric trial dose selection.