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.
Khor
S P
SP
Pharmacokinetic and Pharmacodynamic Sciences, Preclinical Research Development, Genetics Institute, Andover, Massachusetts, USA. akhor@genetics.com
McCarthy
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DuPont
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Murray
K
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Timony
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G
D000465:Algorithms; D000818:Animals; D019540:Area Under Curve; D001792:Blood Platelets / Q000378:metabolism; D001835:Body Weight / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D006207:Half-Life; D000882:Haplorhini; D006801:Humans; D008562:Membrane Glycoproteins / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051379:Mice; D019007:P-Selectin / Q000502:physiology*; D010215:Papio; D051381:Rats; D011994:Recombinant Proteins / Q000493:pharmacokinetics; D013045:Species Specificity; D013552:Swine
D008562:Membrane Glycoproteins; D019007:P-Selectin; C084882:P-selectin ligand protein; D011994:Recombinant Proteins