Predicting dose sparing benefit and bleeding risk of pharmacokinetic-based personalized prophylactic dosing of factor VIII products.

BACKGROUND: Previously published factor VIII (FVIII) pharmacokinetic (PK)-based dosing approaches employ fixed infusion interval with a wide dose range that may lead to increased risk of bleeding, excessive doses or decreased health-related quality of life.

AIM: The objectives of the study includes (i) personalizing infusion interval in lieu of fixed infusion, (ii) constraining dose within the range of 10-50 IU/kg and (iii) characterizing bleeding risk of PK-based dosing in comparison with empiric standard doses.

METHODS: Patient demographics and PK parameters for conventional FVIII products were obtained from published literatures. Subject-specific PK parameters were derived from FVIII activities vs time data generated through simulation.

RESULTS: Our data indicated approximately 4%, 38%, 37% and 20% of the subjects can be dosed with infusion interval of every 24, 48, 72 and 96 hours, respectively, for maintaining a target 1 IU/dL FVIII level within the dose range of 10-50 IU/kg. Maintaining an alternative trough value of 3 or 5 IU/dL requires more frequent infusion. The predicted median probability of bleeding risk per year was 35.7% (range, 11%-49%) for PK-based dosing maintaining 1 IU/dL. Predicted median bleeding risk was 37.9% (0%-74%), 32.8% (0%-72%) and 26.7% (0%-70%) for standard dosing of 20, 30 and 50 IU/kg, respectively. PK-based dosing resulted in a dose sparing benefit compared to standard dose of 30 or 50 IU/kg three times per week.

CONCLUSION: The results of the study demonstrate the feasibility of individualizing infusion interval, restricting FVIII dose, trough and peak concentration within an acceptable range.