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 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 t(1/2) across animal species are well described by power functions with body weight as an independent variable. 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 predict pharmacokinetics of rPSGL-Ig in humans. For a 70-kg human, the values of 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 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 EC(50) 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.

• Publication year

  2000

• Venue

  Journal of Pharmacology and Experimental Therapeutics

• Publication date

  2000-04-01

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1016/s0022-3565(24)39276-6PMID 10773036
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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