Pharmacokinetics and pharmacodynamics of rFVIIa and new improved bypassing agents for the treatment of haemophilia.

Abstract

Animal models have played a critical role in developing our understanding of haemophilia and its treatment. For example, studies in mice and dogs have provided insights into the pharmacokinetics and pharmacodynamics of recombinant activated factor VII (rFVIIa). Such studies have shown that antithrombin has a significant impact on clearance of rFVIIa, which explains discrepancies between the antigen and activity half-lives of rFVIIa. Animal studies have also shown that the major clearance organs for rFVIIa are the liver and the kidneys, whereas distribution studies suggest that FVII and rFVIIa leave the circulation and enter the tissues, before returning to the circulation through the lymph. One agent that has benefited greatly from the use of animal models in its development is vatreptacog alfa, a new analogue of rFVIIa. Promising in vitro results, including increased generation of FXa, shortened clotting times and increased clot stability, were subsequently confirmed in animal models. In a severe tail-bleed model in FVIII knock-out mice, reduction in maximal blood loss was substantially greater with vatreptacog alfa than with rFVIIa, FVIII or plasma-derived activated prothrombin complex concentrate. In a mouse model of joint bleeding, rFVIIa and vatreptacog alfa significantly reduced bleeding compared with vehicle-treated haemophilic controls. More recently, a model of endothelial injury based on mouse cremaster muscle has been developed. Overall, animal models are a valuable tool in elucidating the haemostatic process and the effects of therapeutic agents, although direct extrapolation to the clinical setting should be done with caution.