The pharmacokinetics and pharmacodynamics of single‐dose and multiple‐dose recombinant activated factor VII in patients with haemophilia A or B

Abstract

Summary Monitoring recombinant activated factor VII ( rFVII a) treatment outcomes remains challenging. Thromboelastography ( TEG ) and the thrombin generation assay ( TGA ), measure coagulation dynamics over time and are being assessed as potential methods for evaluating and monitoring haemophilia treatment. Lack of standardized TEG / TGA methods makes it difficult to compare results and to establish a correlation with clinical outcomes. Aims To compare the pharmacokinetics ( PK ) of rFVII a after 3×90 μg kg −1 doses vs a single dose (270 μg kg −1 ) in haemophilia patients and to evaluate TEG / TGA results postdosing to determine how these assays relate to PK findings. Methods Patients in this open‐label, single‐centre, randomized, crossover trial received one injection of 270 μg kg −1 rFVII a crossed over with three injections of 90 μg kg −1 rFVII a in a non‐bleeding state. For TEG , kaolin and tissue factor were used as activators; TGA was performed on frozen platelet‐rich and platelet‐poor plasma, with and without corn trypsin inhibitor. FVII a activity was evaluated using in vivo samples. Results TGA showed a dose‐dependent effect of rFVII a on thrombin generation; TEG revealed lower dose‐dependent effects. Both showed some differences between single‐/multiple‐dose rFVII a; both supported the PK findings. Conclusion While TEG and TGA are not yet clinically predictive, both supported the PK results. Data suggest that, while a single dose of 270 μg kg −1 rFVII a provides slightly higher haemostatic potential than the multiple‐dose regimen of 3×90 μg kg −1 , the latter results in prolonged activity levels compared with a higher single dose.