OC 24.4 - Effect of F8 mutations and Von Willebrand factor on pharmacokinetics of FVIII concentrates in severe hemophilia A

Background: Previous studies showed that FVIII half-life can be influenced by several variables, such as patient’s age and Von Willebrand factor (VWF). A possible influence of the type of F8 mutation has also been hypothesized and studied in small cohorts of patients. However, previous studies could not find a significant effect of specific genotypes on FVIII half-life. Also, these studies have often included patients with severe and moderate hemophilia A. Individualized, PK-tailored prophylaxis is recommended to optimize the therapy of hemophilia A patients and a better understanding of PK determinants would be potentially beneficial.

Aims: To evaluate the influence of F8 mutation and VWF antigen on FVIII half-life in patients with severe hemophilia A.

Methods: Bayesian PK estimates on patients from the Hamilton-Niagara Hemophilia Treatment Center (Ontario, Canada) were extracted from the WAPPS-Hemo database. Genetic mutations and the other relevant information for the same patients were obtained for the same patients from the Canadian Bleeding Disorders Registry. Patients with missense mutations were classified as cross-reacting material positive (CRM+), all the others were considered CRM-. We performed a multivariate regression with terminal half-life as the dependent variable, the following predictors: CRM status, BMI, age, type of product [standard versus extended half-life (SHL vs EHL)], VWF antigen (Ag), and the interaction between the type of product and VWF Ag.

Results: A total of 63 individual PK studies were available for analysis. The patients’ characteristics are reported in Table 1. The CRM status appeared not to be associated with the half-life (Fig 1). In the multivariate regression (Table 1), the only statistically significant predictor was the VWF antigen, showing that the adjusted mean increase in the half-life is 3.91 hours per unit (IU/mL) increase of VWF.

Conclusion(s): The VWF antigen is the only predictor, among those included, significantly associated with the FVIII half-life in our regression model.