PB0674 - The Impact of Suboptimal Adherence to Factor Replacement Therapy on Time Spent Below Target Factor Trough Levels: Simulations Using Population Pharmacokinetic Modeling

Background: The current standard of care for people with hemophilia includes prophylaxis with factor VIII (FVIII) or IX (FIX) replacement therapy. Suboptimal adherence to prophylaxis is expected to lead to higher rates of bleeding due to more time spent below a designated factor activity trough level. Approaches to modeling the impact of suboptimal adherence are limited.

Aims: To simulate the impact of missed doses on time spent below target trough levels, using a novel population pharmacokinetic (PK) modeling approach incorporating suboptimal adherence to standard half-life (SHL) or extended half-life (EHL) factor replacement therapy.

Methods: Virtual populations of 500 individuals (weight: 50–100 kg) were generated. Individual PK parameters were randomly sampled from normal distributions defined by previous population PK models, derived from nonacog alfa (FIX-SHL), eftrenonacog alfa (FIX-EHL), moroctocog alfa (FVIII-SHL), or efmoroctocog alfa (FVIII-EHL). Factor replacement doses were simulated to steady state (~9 doses), and the impact of missed doses on factor levels was assessed. The percentage of time spent below target troughs (3%, 5%, 10%, 20%, 30%) was summarized using median and 90% confidence intervals.

Results: Adherence simulations (Table, Figure) estimated that with conventional target trough levels (eg, 3–5%), suboptimal adherence (1 or 2 missed doses) increased median time spent below trough level. The impact of suboptimal adherence was not mitigated when modeling EHL vs SHL therapies. Even with perfect adherence (ie, 0 missed doses), and regardless of use of SHL or EHL, most modeled individuals’ time was spent below a factor activity of 20%.

Conclusion(s): These data illustrate the potential impact of suboptimal adherence to prophylaxis on time spent below FVIII and FIX trough levels. Perfect adherence using the modeled regimens did not maintain factor activity >20%. Innovative strategies that can reduce suboptimal adherence and/or increase time spent within factor activity ranges associated with minimal bleeding (>20%) are needed.