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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Pharmacokinetics, Pharmacodynamics, Allometry, and Dose Selection of rPSGL-Ig for Phase I Trial

Soo Peang Khor, Kyle McCarthy, Michelle DuPont, Kristin Murray and Gregg Timony
Journal of Pharmacology and Experimental Therapeutics May 2000, 293 (2) 618-624;
Soo Peang Khor
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Kyle McCarthy
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Michelle DuPont
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Kristin Murray
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Gregg Timony
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Abstract

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.

Footnotes

  • Send reprint requests to: Soo Peang Khor, One Burtt Rd., Andover, MA 01810. E-mail: skhor{at}genetics.com

  • Abbreviations:
    PSGL-1
    P-selectin glycoprotein ligand-1
    DVT
    deep vein thrombosis
    ELISA
    enzyme-linked immunosorbent assay
    MOPS
    4-morpholinepropanesulfonic acid
    CL
    clearance
    AUC
    area under the serum concentration-time curve
    • Received November 5, 1999.
    • Accepted January 27, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 293 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 293, Issue 2
1 May 2000
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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Pharmacokinetics, Pharmacodynamics, Allometry, and Dose Selection of rPSGL-Ig for Phase I Trial

Soo Peang Khor, Kyle McCarthy, Michelle DuPont, Kristin Murray and Gregg Timony
Journal of Pharmacology and Experimental Therapeutics May 1, 2000, 293 (2) 618-624;

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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Pharmacokinetics, Pharmacodynamics, Allometry, and Dose Selection of rPSGL-Ig for Phase I Trial

Soo Peang Khor, Kyle McCarthy, Michelle DuPont, Kristin Murray and Gregg Timony
Journal of Pharmacology and Experimental Therapeutics May 1, 2000, 293 (2) 618-624;
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