Modeling and Simulation to Inform Apixaban Dosing in Pediatrics With Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma Treated With Asparaginase

Abstract

Apixaban could be a potential treatment option for the prevention of venous thromboembolism (VTE) in children with acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL). This analysis describes an updated two-compartment population pharmacokinetic (PPK) model that characterizes the PK variability of apixaban in pediatric patients with ALL or LL treated with asparaginase using PK data from a phase III study (PREVAPIX). Patient type of ALL or LL was found to be a significant covariate on the apparent central volume of distribution (Vc/F) and first-order absorption rate (Ka). Pediatric patients (aged 9 months to < 18 years) with ALL or LL had a 52.4% lower Ka compared with adults; this was 81.1% lower than other pediatric patients (9 months to < 18 years) at risk of VTE. Apixaban Vc/F was estimated to be 43.1% lower in pediatric patients compared with adult patients. The updated PPK model was used to simulate and confirm apixaban fixed-dose by weight-tiered regimen-achieved target exposures in pediatric patients (aged 28 days to < 18 years) with ALL or LL. In addition, a PK/pharmacodynamic (PD) analysis was performed using a linear regression model to characterize the relationship between anti-FXa activity (AXA) and apixaban concentration in pediatric patients with ALL or LL. The characterization of apixaban PK and PK/PD in this analysis contributes to evidence that apixaban could be a potential antithrombotic option in pediatric patients.