| Abstract: | SB-249417, a humanized monoclonal antibody (Mab) specific for the Gla domain of Factor IX, inhibits activation of this zymogen and blocks the activity of Factor IXa on Factor X, the subsequent enzyme in the clotting cascade. In the present study, the pharmacokinetics and pharmacodynamics of SB-249417 were investigated in male Sprague-Dawley rats after IV administration of single doses of 10, 50, or 250 mg/kg. Blood samples were collected for up to six weeks to assess total plasma Mab concentration and activated partial thromboplastin time (aPTT). A PK/PD model was developed using an empirical relationship between aPTT and the concentration of free Factor IX (inhibitory Emax model). The model assumed natural synthesis and degradation of the endogenous zymogen that was interrupted by the complexation of Factor IX with the antibody. Following antibody administration, aPTT values increased 5-fold above baseline at the earliest sampling time in all dose groups. Higher doses led to a longer duration of prolonged clotting time. Estimates of model parameters yielded a Kd for antibody-antigen interaction (38 nM) that was similar to the in vitro value. The estimated degradation half-life of Factor IX (8 hr) was consistent with historical estimates. The PK/PD model predicted that the maximum concentration of antibody-Factor IX complex (Cmax) and the time to Cmax (Tmax) would increase with increasing dose. The extent of accumulation, up to 10-fold greater than the concentration of endogenous Factor IX at baseline, was confirmed by Western Blot analysis of Protein A extracts. Complex Tmax was similar to the duration of pharmacological effect and suggests effects persisted until Factor IX synthesis produced sufficient antigen to saturate the antibody. |
