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

Abstract

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.

Pharmacodynamic monitoring of factor VIII replacement therapy in hemophilia A: Combining thrombin and plasmin generation

“…This approach has recently been tested in a study that showed an increased frequency of spontaneous bleeding in HA patients with reduced TG regardless of FVIII trough levels when patients were on personalized prophylaxis with human‐cl rhFVIII (Nuwiq) 9 . A follow‐up study postulated a PK/PD non‐linear relationship between FVIII and ETP, thereby creating a dosing tool for this FVIII product to even further personalize FVIII prophylaxis 40 …”

“…9 A follow-up study postulated a PK/PD non-linear relationship between FVIII and ETP, thereby creating a dosing tool for this FVIII product to even further personalize FVIII prophylaxis. 40 Our goal is to use our PD data to develop a uniform model to individualize FVIII replacement therapy based on PK/PD data for a range of FVIII products. A concomitant advantage of PD analysis is that factors influencing the hemostatic balance, such as operative stress and inflammation, are also taken into account, and thereby possibly reduce FVIII product need.…”

Thrombin generation assay modifications needed for its application to monitoring of replacement therapy for haemophilia

“…Surprisingly, only a few studies demonstrated that reduced TG correlates with increased bleeding in haemophilia. 4 In addition, com- Another problem of the TF-triggered TG assay is its extreme sensitivity to activated FIX (FIXa), a product-related impurity found in all licensed FIX concentrate products. 5,6 One recombinant FIX concentrate (used in a spiking paper 2 ) was shown to contain higher FIXa levels than most other FIX products.…”

Variability of treatment modalities and intensity in patients with severe haemophilia A on prophylaxis: Results from the Italian national registry

“…More recently, a shift from a standard to a personalized prophylaxis has been increasingly adopted 4‐8 . Personalized prophylaxis is based on different characteristics in addition to the bleeding phenotype.…”