LAUSR

BACKGROUND Model-informed personalized prophylaxis with factor VIII (FVIII) replacement therapy aimed at higher trough levels is becoming indispensable for patients with severe hemophilia A. This study aimed to identify the most suitable population pharmacokinetic (PK) models for personalized prophylaxis using various FVIII products and two clinical assays and to implement the most suitable one in an open-access software. METHODS Twelve published population PK models were systematically compared to predict the time above target (TaT) for a reference dosing occasion. External validation was performed using five-point PK data from 39 adult hemophilia A patients with FVIII measured by chromogenic substrate (CSA) and one-stage assays (OSA) using NONMEM under three different conditions: a priori (with all FVIII samples blinded), a posteriori (with one trough sample), and general model fit (with all FVIII samples including the reference dosing occasion provided). RESULTS On average, the baseline covariate models overpredicted TaT (a priori; bias -3.8 h to 49.6 h). When additionally including one previous trough FVIII sample before the reference dosing occasion (a posteriori), only 50% of the models improved in bias (-1.0 h to 36.5 h) and imprecision (22.4 h and 60.7 h). Using all the time points (general model fit), the models accurately predicted (individual TaT less than ±12 h compared to the reference) 62%-90% and 33%-74% of the patients using CSA and OSA data, respectively. Across all scenarios, predictions using CSA data were more accurate than those using the OSA data. CONCLUSIONS One model performed best across the population (bias: -3.8 h a priori, -1.0 h a posteriori, 0.6 h general model fit) and acceptably predicted 44% (a priori) to 90% (general model fit) of the patients. To allow the community-based evaluation of patient-individual FVIII dosing, this model was implemented in the open-access model-informed precision dosing software 'TDMx.'