Pharmacokinetics, pharmacodynamics, allometry, and dose selection of rPSGL-Ig for phase I trial

rPSGL-Ig is a recombinant, soluble, and chimeric form of P-selectin glycopr otein ligand-1, which is developed as an antagonist to P-selectin. Allometr ic and pharmacokinetic/pharmacodynamic modeling was used to select doses fo r human clinical trials. Pharmacokinetic parameters of rPSGL-Ig such as cle arance (CL), volume of distribution (Vc), and t(1/2) across animal species are well described by power functions with body weight as an independent va riable. The power functions for CL, Vc, and t(1/2) were CL = 0.37.W-0.93 ml /h (r(2) = 0.94), Vc = 45.0.W-1.064 ml (r(2) = 0.988), and t(1/2) = 190.W-0 .159 h (r(2) = 0.75), respectively. These functions provide a means to pred ict pharmacokinetics of rPSGL-Ig in humans. For a 70-kg human, the values o f CL, Vc, and t(1/2) are predicted to be 19.9 ml/h, 4138 ml, and 15.5 days, respectively. The predicted pharmacokinetics in humans is used in conjunct ion with pharmacological data to estimate appropriate doses for clinical tr ials. The doses that may provide potential effects in humans range from 0.1 3 to 4.7 mg/kg. The predicted doses produce concentrations above those that are associated with efficacy in animal disease models and, maintain concen trations above the EC50 of in vitro binding between rPSGL-Ig and stimulated human platelets. Hence, rPSGL-Ig in clinical trials may provide therapeuti c activities for P-selectin-mediated diseases.