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.