Clinical Predictors and Prediction Models for rFVIII-Fc Half Life in Real-World People with Severe Hemophilia A

Authors: Chang, C-Y; Chiou, S-S; Weng, T-F; Lin, P-C; Lai, S-W; Tsai, C-H; Liu, Y-L; Ku, J-T; Liao, Y-M; Tsai, J-R; Hu, S-H; Cheng, C-N; Chen, Y-C

Affiliations: Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.

Publication: Journal of Clinical Medicine ; 2023 ; 12

Abstract: The half-life of recombinant factor VIII-Fc (rFVIII-Fc) for people with hemophilia A (PwHA) varies greatly. Understanding the factors influencing the variation and assessment of rFVIII-Fc half-life is important for personalized treatment. Eighty-five severe-type PwHA with rFVIII-Fc treatment receiving an evaluation of half-life by the Web-Accessible Population Pharmacokinetic (PK) Service-Hemophilia during 2019-2021 were retrospectively enrolled. The 50-patient PK profiles before 2021 were used for analysis and developing prediction models of half-life, and the 35-patient PK profiles in 2021 were used for external validation. The patients in the development cohort were aged 8-64, with a median rFVIII-Fc half-life of 20.75 h (range, 8.25-41.5 h). By multivariate linear regression analysis, we found two, four, and five predictors of rFVIII-Fc half-life for the blood groups non-O, O patients, and overall patients, respectively, including baseline VWF:Ag, BMI, VWF:activity/VWF:Ag ratio, body weight, O blood group, inhibitor history, HCV infection, and hematocrit. The three prediction equations of rFVIII-Fc half-life (T) were respectively developed as T for non-O group patients = -0.81 + 0.63 × (BMI, kg/m(2)) + 6.07 × (baseline VWF:Ag, IU/mL), T for O group patients = -0.68 + 13.30 × (baseline VWF:Ag, IU/mL) + 0.27 × (BW, kg) – 1.17 × (BMI, kg/m(2)) + 16.02 × (VWF:activity/VWF:Ag ratio), and T for overall patients = -1.76 + 7.24 × (baseline VWF:Ag, IU/mL) – 3.84 × (Inhibitor history) + 2.99 × (HCV infection) – 2.83 × (O blood group) + 0.30 × (Hct, %), which explained 51.97%, 75.17%, and 66.38% of the half-life variability, respectively. For external validation, there was a significant correlation between the predicted and observed half lives in the validation cohort. The median half-life deviation was +1.53 h, +1.28 h, and +1.79 h for the equations of non-O group, O group, and overall group patients, respectively. In total, eight predictors influencing rFVIII-Fc half-life were identified. Prediction equations of rFVIII-Fc half-life were developed for the non-O and O blood groups and overall PwHA with a good degree of external validation. The equations could be applied to patients aged 8-64 without the need for PK blood sampling and clinically valuable for personalized therapy.