Pharmacokinetics and pharmacodynamics of a humanized monoclonal antibody to factor IX in cynomolgus monkeys

The pharmacokinetics and pharmacodynamics (PK/PD) of a humanized anti-Facto r IX IgG1 monoclonal antibody (SB 249417, FIX mAb) were studied in Cynomolg us monkeys. Single i.v. bolus doses of 1, 3, or 10 mg/kg of FIX mAb were ad ministered. The total FIX mAb concentration, activated partial thromboplast in time (aPTT), and Factor IX activity were monitored for up to 4 weeks aft er dosing. In the monkey, FIX mAb had a plasma clearance of 0.6 ml/h/kg and a steady-state volume of distribution of approximately 70 ml/kg. The elimi nation phase half-life (3.8 days) was considerably less than other humanize d IgG1 mAbs in the monkey, for which there is no binding to endogenous anti gen. The suppression of Factor IX activity and the prolongation of aPTT wer e rapid and dose dependent. The time for aPTT values to return to basal lev els (25-170 h) increased with increasing dose. A mechanism-based PK/PD mode l consistent with the stoichiometry of binding (2:1) was developed to descr ibe the Factor IX activity and aPTT response time course. The model incorpo rated Factor IX synthesis and degradation rates that were interrupted by th e sequestration of Factor IX by the antibody. aPTT values were related to f ree Factor IX activity. This model was able to describe the PD profiles fro m the three dose levels simultaneously. The estimated Factor IX half-life w as 11 h and the third-order association rate constant was 3.96 x 10(3) mu M -2 h(-1). The PK/PD modeling was useful in summarizing the major determinan ts (endogenous and antibody-ligand binding) controlling FIX mAb-related eff ects.