Bayesian Forecasting Utilizing Bleeding Information to Support Dose Individualization of Factor VIII.

Bayesian forecasting for dose individualization of prophylactic factor VIII replacement therapy using pharmacokinetic samples is challenged by large interindividual variability in the bleeding risk. A pharmacokinetic-repeated time-to-event model-based forecasting approach was developed to contrast the ability to predict the future occurrence of bleeds based on individual (i) pharmacokinetic, (ii) bleeding, and (iii) pharmacokinetic, bleeding and covariate information using observed data from the Long-Term Efficacy Open-Label Program in Severe Hemophilia A Disease (LEOPOLD) clinical trials (172 severe hemophilia A patients taking prophylactic treatment). The predictive performance assessed by the area under receiver operating characteristic (ROC) curves was 0.67 (95% confidence interval (CI), 0.65-0.69), 0.78 (95% CI, 0.76-0.80), and 0.79 (95% CI, 0.77-0.81) for patients ≥ 12 years when using pharmacokinetics, bleeds, and all data, respectively, suggesting that individual bleed information adds value to the optimization of prophylactic dosing regimens in severe hemophilia A. Further steps to optimize the proposed tool for factor VIII dose adaptation in the clinic are required.