Limited sampling strategies for individualized BAX 855 prophylaxis in severe hemophilia A: in silico evaluation

Purpose: Limited sampling strategies (LSS) lower the burden of PK-guided dosing, but an extensive evaluation of LSS for BAX 855 (Adynovi®) is currently lacking. This study aimed to develop a LSS for BAX 855 and combine this with a LSS of a standard half-life (SHL) FVIII concentrate in a clinical setting. Methods: Individual PK parameters of BAX 855 were estimated for 10,000 virtual patients with severe hemophilia A using Monte Carlo simulations. Several LSS consisting of 2-6 samples were examined based on patient burden, bias and accuracy of clearance, elimination half-life, volume of distribution and trough levels at 72h (C72). Analyses were performed separately for adults and children <12 years. Results: The preferred LSS for BAX 855 consisted of three sampling points at 15-30 min, 48h and 72h for both adults (mean accuracy C72: 14.0% vs. 10.8% using six samples) and children (mean accuracy C72: 14.9% vs. 11.4% using six samples). The best strategy with two samples (peak, 48 hours) resulted in an adequate, but lower accuracy than strategies with ≥3 samples (mean accuracy C72: 22.3%). The optimal combination of the LSS of SHL FVIII and BAX 855 led to six samples during four clinical visits. Conclusion: This in silico study has identified that two to three samples are necessary to estimate the individual PK of BAX-855 adequately. These samples can be collected in one or two clinical visits. When combining PK profiling of SHL FVIII and BAX 855, six samples during four clinical visits are needed.