PII-063 - MODELING AND SIMULATION TO SUPPORT APIXABAN DOSE RECOMMENDATION FOR THROMBOEMBOLISM PREVENTION IN PEDIATRIC SUBJECTS WITH CONGENITAL OR ACQUIRED HEART DISEASE REQUIRING ANTICOAGULATION – SAXOPHONE STUDY.

T. Ajavon-Hartmann¹, P. Jarugula¹, H. Back¹, O. Obianom², E. Ludwig², C. Crevar¹, D. Marchisin¹, Z. Wang¹, W. Chen¹, B. He¹, V. Perera¹, B. Murthy¹, S. Merali¹; ¹Bristol Myers Squibb, Lawrenceville, NJ, USA, ²Simulations Plus Inc., Buffalo, NY, USA.

Background: Apixaban could be a treatment option for thromboembolism prevention in children with congenital or acquired heart disease (CAHD). This analysis characterized apixaban pharmacokinetics (PK) and PK/pharmacodynamics (PD) in pediatric patients (pts) with CAHD to evaluate dosing.

Methods: Data from a Phase 2 pediatric study (NCT02981472, N = 124) were used to update a previously developed population PK model and assess the covariate effect of pt type on PK parameters, while retaining previous covariates. Stochastic simulations were performed to assess whether proposed doses in pediatric pts aged 28 days to < 18 years matched adult exposures (5 mg bid). The relationship between anti-factor Xa (AXA) and apixaban concentration was also evaluated.

Results: Apixaban apparent clearance was modestly lower (~21%) in pediatric pts with CAHD compared with adults. Simulations of proposed fixed doses by weight tiers demonstrated apixaban steady-state exposures in pediatric pts were consistent with adult exposures and were maintained in virtual pts with dose adjustments (Figure). The apixaban PK–AXA relationship was characterized well using a linear mixed effects model.

Conclusion: Apixaban PK and PK/PD were well characterized. Proposed dosing regimens for pediatric pts with CAHD were confirmed to match adult exposures.

Comparison of (A) Simulated Exposures Between Virtual Pediatric Patients Aged 28 Days to < 18 Years by Weight Tiers and the Adult VTEtx Population and Non-valvular Atrial Fibrillation (ARISTOTLE) Study Population* and (B) Apixaban Predicted Trough Concentrations From Simulations of the Weight-Based Dose Adjustment Paradigm in Virtual CAHD Subjects Aged < 2 Years and > 2 Years to Assess if the Paradigm Was Adequate in Matching Adult Exposures†