| Autor: |
Garonzik, Samira M, Byon, Wonkyung, Patel, Yogesh, Elsrougy, Amira, Marchisin, David, Perera, Vidya, Chen, Weidong, He, Bing, Murthy, Bindu |
| Zdroj: |
Circulation (Ovid); November 2021, Vol. 144 Issue: Supplement 1 pA10571-A10571, 1p |
| Abstrakt: |
Introduction:Standard-of-care antithrombotics in pediatric subjects (peds) include unfractionated/LMW heparin, aspirin, and vitamin K antagonists. Apixaban, a direct factor Xa (FXa) inhibitor indicated for VTE treatment (tx) and prevention in adults, may be an effective and convenient oral tx option with an acceptable safety profile in peds.Objectives:To evaluate pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of apixaban in peds at risk for venous or arterial thrombotic disorder; to support dose selection for apixaban pediatric program trials.Methods:This phase 1 study (NCT01707394) enrolled peds aged < 18 years (y) at risk for venous/arterial thrombotic disorder into groups by age. Peds undergoing tx/procedures or with conditions that may affect bleeding risk or apixaban exposure were excluded. A single apixaban dose (based on BSA; targeted to achieve adult exposures with apixaban 2.5 mg) was administered: 0.1 mg sprinkle capsule for age < 28 days (d); 0.4 mg/mL solution for ages 28 d to < 18 y (dose range: 1.08-2.19 mg/m2). Endpoints included PK, safety, tolerability, and PD (anti-FXa activity). For PK/PD, 4-6 blood samples were collected ≤ 26 h after dosing. A population PK (PPK) model developed with data from adults and peds was used to evaluate PK. Apparent oral clearance (CL/F) included a fixed maturation function based on published data.Results:From Jan 2013 to Jun 2019, 49 peds aged 9 d to 16 y received an apixaban dose. All AEs (n = 15) resolved; most were mild/moderate; none were bleeding-related. SAEs (1 seizure; 1 limb venous thrombosis) were not tx-related. 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 ages 12 to < 18 y. Maturation affected CL/F most notably in ages < 9 months. Plasma anti-FXa activity values were linearly related to apixaban concentrations with no apparent age-related differences, comparable to adults.Conclusions:Single apixaban doses were generally safe and well tolerated in peds. Study data and PPK model supported dose selection for phase 2/3 multiple-dose pediatric trials. |
| Databáze: |
Supplemental Index |
| Externí odkaz: |
|
