A new paradigm for personalized prophylaxis for patients with severe haemophilia A.

AIM: For patients with severe haemophilia A, guidelines recommend prophylactic treatment with FVIII, with dose calculations targeting a predetermined FVIII trough level. However, this pharmacokinetic (PK) approach is suboptimal, with some patients experiencing breakthrough bleeds. We aimed to improve FVIII dosing by incorporating the thrombin generation assay, a global haemostasis assay whose main pharmacodynamic (PD) parameter, endogenous thrombin potential (ETP), predicts spontaneous bleeding risk. METHODS: We performed post hoc combined PK-PD modelling using data from 66 adults who received human-cl rhFVIII (Nuwiq® , Octapharma AG) in a phase IIIb study. Time-to-event analyses simulated the probability of spontaneous bleeding for different FVIII exposures and baseline ETPs. RESULTS: Ninety-one spontaneous bleeds occurred in 20/66 patients. The relationship between FVIII:C and ETP was non-linear, and the sigmoid Emax model adequately described the data. Individual PK-PD Bayesian estimation significantly improved predictive performance. Simulations showed that the mean spontaneous annual bleeding rate decreased with increasing baseline ETP or dosing: with ETP values of 200, 400 and 600 (nmol/L)·min annual bleeding rates were 2.36, 1.25 and 0.66, respectively, on 40 IU/kg human-cl rhFVIII every 3 days; and annual bleeding rates were 2.09, 1.10, and 0.60, respectively, on 60 IU/kg every 3 days. CONCLUSION: Prophylactic FVIII dosing is more clinically meaningful when incorporating ETP alongside FVIII level. For the first time, FVIII dosing can be personalized with the aim of eliminating spontaneous breakthrough bleeds.