Characterization of Apixaban Pharmacokinetics/Pharmacodynamics and Dose Assessment in Pediatric Patients with Congenital or Acquired Heart Disease

Abstract

Apixaban is an oral direct inhibitor of factor Xa (FXa) that could be a treatment option for thromboembolism prevention in children with congenital or acquired heart disease (CAHD). Data from SAXOPHONE, a phase II pediatric study, were used to update a previously developed population pharmacokinetics (PPK) model and to assess the covariate effect of patient type on PK parameters while retaining previous covariates. Stochastic simulations were performed to assess whether the proposed dosing regimens in pediatric patients aged 28 days to < 18 years matched adult exposures. The relationship between anti-Factor Xa (AXA) and apixaban concentration, as well as apixaban concentration and chromogenic FX, were evaluated. Apixaban dose adjustment in response to the growth of pediatric patients and changes in age and weight were also assessed. Apixaban PK in pediatric patients with CAHD was well characterized by a 2-compartment model with first-order absorption, dose-dependent F1, and first-order elimination. Apixaban apparent clearance (CL/F) and apparent volume of distribution in the central compartment (Vc/F) increased with increasing body weight. Apixaban CL/F was lower in pediatric patients with CAHD compared to adults and other pediatric patients. The fixed dose by weight-tiered dosing regimen for pediatric patients with CAHD (28 days to < 18 years) achieved target exposures similar to adult VTE treatment and nonvalvular atrial fibrillation populations. A linear PK/PD relationship between apixaban and AXA was observed. Inhibition of FXa was observed across weight tiers. Apixaban dose adjustment in response to weight gain resulted in exposures similar to target adult exposures.

Figure 1

Goodness‐of‐fit plots of the apixaban final population pharmacokinetic model, overall and in pediatric patients with CAHD. Data from this figure were previously presented at the American Society for Clinical Pharmacology & Therapeutics (ASCPT) 2023 Annual Meeting; March 22–24, 2023; Atlanta, GA, USA. Poster PII‐063. CAHD, congenital or acquired heart disease; |IWRES|, absolute individual weighted residuals; VTE, venous thromboembolism.

Figure 2

Body weight adjusted CL/F versus age plot with overlaid maturation function for (a) all patients and (b) pediatric patients <5 years of age. Line represents maturation function. CL/F, apparent clearance.

Figure 3

Comparison of simulated exposures between virtual pediatric patients aged 28 days to < 18 years by weight tiers and the adult VTEtx population and ARISTOTLE study. Data from this figure were previously presented at the American Society for Clinical Pharmacology & Therapeutics (ASCPT) 2023 Annual Meeting; March 22–24, 2023; Atlanta, GA, USA. Poster PII‐063. The red dashed line and shaded region represent the median, 5th percentile, and 95th percentile of exposure in the adult population. Values in the box represent the median steady‐state AUC_TAU in the adult ARISTOTLE and VTEtx studies and at each weight tier for pediatrics in the SAXOPHONE study. Open circles in the body weight–tiered box plots denote model‐predicted exposures for pediatric patients, and for the adult ARISTOTLE and VTEtx studies, the open circles represent observed exposures. AUC_TAU, area under the concentration versus time curve over the dosing interval; VTEtx, venous thromboembolism treatment.

Figure 4

Visual predictive check of the final apixaban pharmacokinetic/pharmacodynamic model for anti‐FXa activity. Data from this figure were previously presented at the American Society for Clinical Pharmacology & Therapeutics (ASCPT) 2023 Annual Meeting; March 22–24, 2023; Atlanta, GA, USA. Poster PII‐063. Conc, concentration; FXa, factor Xa.