PT - JOURNAL ARTICLE AU - Soo Peang Khor AU - Kyle McCarthy AU - Michelle DuPont AU - Kristin Murray AU - Gregg Timony TI - Pharmacokinetics, Pharmacodynamics, Allometry, and Dose Selection of rPSGL-Ig for Phase I Trial DP - 2000 May 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 618--624 VI - 293 IP - 2 4099 - http://jpet.aspetjournals.org/content/293/2/618.short 4100 - http://jpet.aspetjournals.org/content/293/2/618.full SO - J Pharmacol Exp Ther2000 May 01; 293 AB - rPSGL-Ig is a recombinant, soluble, and chimeric form of P-selectin glycoprotein ligand-1, which is developed as an antagonist to P-selectin. Allometric and pharmacokinetic/pharmacodynamic modeling was used to select doses for human clinical trials. Pharmacokinetic parameters of rPSGL-Ig such as clearance (CL), volume of distribution (Vc), and t1/2 across animal species are well described by power functions with body weight as an independent variable. The power functions for CL,Vc, and t1/2 were CL = 0.37·W0.93 ml/h (r2 = 0.94), Vc = 45.0·W1.064 ml (r2 = 0.988), andt1/2 = 190·W0.159 h (r2 = 0.75), respectively. These functions provide a means to predict pharmacokinetics of rPSGL-Ig in humans. For a 70-kg human, the values of CL, Vc, andt1/2 are predicted to be 19.9 ml/h, 4138 ml, and 15.5 days, respectively. The predicted pharmacokinetics in humans is used in conjunction with pharmacological data to estimate appropriate doses for clinical trials. The doses that may provide potential effects in humans range from 0.13 to 4.7 mg/kg. The predicted doses produce concentrations above those that are associated with efficacy in animal disease models and, maintain concentrations above the EC50 of in vitro binding between rPSGL-Ig and stimulated human platelets. Hence, rPSGL-Ig in clinical trials may provide therapeutic activities for P-selectin-mediated diseases. The American Society for Pharmacology and Experimental Therapeutics