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Clinical Trial
. 2023 Apr;12(4):500-512.
doi: 10.1002/psp4.12935. Epub 2023 Mar 5.

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

Samira J Merali  1 , Wonkyung Byon  2 , Yogesh T Patel  3 , Amira Elsrougy  1 , David Marchisin  1 , Vidya Perera  1 , Weidong Chen  1 , Bing He  1 , Bindu Murthy  1
Affiliations
Clinical Trial

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

Samira J Merali et al. CPT Pharmacometrics Syst Pharmacol. 2023 Apr.

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.

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Conflict of interest statement

S.J.M., A.E., D.M., V.P., B.H., and B.M. are employees of and shareholders in Bristol Myers Squibb. W.B. was an employee of and shareholder in Pfizer at the time the study took place (currently an employee at Amador Bioscience, Ann Arbor, MI, USA). Y.T.P. reports Cognigen Corp received support from Bristol Myers Squibb to perform the model‐based analysis described in the manuscript. W.C. is an employee of Bristol Myers Squibb.

Figures

FIGURE 1
FIGURE 1
Study design. *Based on 16 subjects aged 2 to <6 years, 6 to <12 years, and 12 to <18 years to confirm or adjust the dose for subjects aged 9 months to <2 years. †Based on four subjects aged 9 months to <2 years and subjects from older age groups to confirm or adjust the dose for subjects aged 28 days to <9 months. ‡Based on all subjects aged 28 days to <18 years to confirm or adjust the dose from birth to age 27 days. §Based on all subjects in all groups who were enrolled prior to study termination.
FIGURE 2
FIGURE 2
Observed apixaban concentration versus time on a semilog scale stratified by age group in pediatric subjects.
FIGURE 3
FIGURE 3
Model‐estimated individual apparent clearance versus age.
FIGURE 4
FIGURE 4
Observed plasma anti‐FXa level versus apixaban concentration, stratified by age. FXa, factor Xa.
See this image and copyright information in PMC

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