Introduction Apixaban is an oral, direct, selective factor Xa (FXa) inhibitor approved in the US (ELIQUIS® [apixaban]. US Prescribing Information. Bristol Myers Squibb, 2025) for treatment of venous thromboembolism (VTE) and prevention of recurrent VTE in pediatric patients from birth to <18 years of age after at least 5 days of initial anticoagulant treatment. To support the apixaban fixed-dose by body weight-tiered regimen in pediatrics aged ≥28 days, a previous pharmacometrics analysis was performed (Ravva P, et al. Presented at ISTH 2025; Washington, DC, USA. Abstract PB0962). This modeling and simulation pharmacometrics analysis aimed to characterize apixaban pharmacokinetics (PK) and confirm the fixed-dose by body weight-tiered regimen for neonatal patients (patients aged <28 days). This analysis also evaluated the relationship between apixaban concentration and anti-FXa (AXA) activity in neonates.

Methods Population PK analysis in neonates was performed by incorporating available apixaban neonatal data into a previously developed model. The final model included data from 746 patients (198 adults, 548 pediatrics), including 144 pediatric patients from a completed phase 4 randomized, open-label, active-controlled trial (NCT02464969) of apixaban in pediatric patients with VTE. The impact of cytochrome P450 (CYP) maturation on apixaban apparent clearance (CL/F) was also considered in the model. For the neonate analysis, a study protocol-specified neonatal PK subanalysis was performed with an initial 6 apixaban-treated neonate patients with evaluable PK data in the phase 4 study, with a final PK analysis performed after study completion and incorporation of an additional 4 apixaban-treated neonate patients (total of 10 apixaban-treated neonate patients). The results from the final analysis of neonates are presented here. Model-based stochastic simulations were performed to estimate median steady-state apixaban exposures that were then compared to exposures from studies in adults with VTE. A PK/pharmacodynamic analysis using time-matched apixaban concentration and AXA data from 3 apixaban pediatric studies (n=390; NCT02464969, NCT02369653, NCT02981472) was performed.

Results The final PK model was a 2-compartment model with first-order absorption, dose-dependent bioavailability, and first-order elimination. Neonates had a mean baseline age of 0.0556 years (standard deviation [SD] 0.011) and body weight of 3.41 kg (SD 0.623). The estimated mean apixaban CL/F in neonates was 0.169 L/h. Once normalized by body weight, apixaban CL/F was lower in neonates, reflecting the influence of maturation of CYP-mediated metabolism. Model diagnostics showed that the final population PK model described the observed data in neonatal subjects well. Model-based stochastic simulated day 7 and steady-state median exposures in neonates receiving apixaban 0.3 mg twice daily (BID) for 7 days followed by 0.15 mg BID thereafter were similar to those previously shown to be safe and effective in the treatment of adult patients with VTE (5 mg BID). The apixaban–AXA relationship in the pediatric population was linear, with a slope close to 1 (0.926).

Conclusions Pharmacometric analysis supported an apixaban fixed-dose by weight-tiered regimen for neonates. Stochastic simulated exposures in neonates were similar to therapeutic levels observed in adult patients with VTE treated with apixaban, supporting the approved (ELIQUIS® [apixaban]. US Prescribing Information. Bristol Myers Squibb, 2025) pediatric dosing strategy in neonates.

Study support Study and professional writing support were funded by Pfizer/Bristol Myers Squibb.

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2025
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