Effect of von Willebrand factor on the pharmacokinetics of recombinant human platelet glycoprotein Ibalpha-immunoglobulin G1 chimeric proteins.

Abstract:

PURPOSE:Recombinant human platelet glycoprotein Ibalpha-immunoglobulin G1 chimeric proteins (GPIbalpha-Ig) have varying levels of anti-thrombotic activities based on their ability to compete for platelet mediated adhesion to von Willebrand Factor (vWF). Valine substituted GPIbalpha-Ig chimeras, at certain position, increase the binding affinity to vWF over its "wild-type" GPIbalpha-Ig analog. The purpose of this study was to determine the pharmacokinetics of two valine substituted GPIbalpha-Ig chimeras, GPIbalpha-Ig/1V (valine substitution at 239 position) and GPIbalpha-Ig/2V (double valine substitution at 233 and 239 position), in mice, rats and dogs. METHODS:Head-to-head comparisons of pharmacokinetics of GPIbalpha-Ig/1V and GPIbalpha-Ig/2V were investigated in rats and dogs after intravenous administration. Since vWF precipitates in the serum but not in plasma preparation, the concentration-time profiles of GPIbalpha-Ig/2V in rats were examined from the same blood samples for determination of matrix effect. The disposition of GPIbalpha-Ig/2V was also compared in vWF-deficient versus wild-type mice. RESULTS:For GPIbalpha-Ig/2V, the serum clearances were 2.62+/-0.27 ml/hr/kg in rats and 1.97+/-0.24 ml/hr/kg in dogs. The serum clearances of less potent GPIbalpha-Ig/1V were 1.08+/-0.08 and 0.97+/-0.19 ml/hr/kg in rats and dogs, respectively. In addition, the serum clearance of GPlbalpha-Ig/2V of 1.53 ml/hr/kg in vWF-deficient mice was lower than that in wild-type mice of 2.79 ml/hr/kg. CONCLUSION:The difference in disposition for valine substituted forms of GPIbalpha-Ig in laboratory animals are likely affected by their enhanced binding affinity for circulating vWF.

journal_name

Pharm Res

journal_title

Pharmaceutical research

authors

Wang Q,Shorten D,Xu X,Shaw GD,Schaub RG,Shea C,Brooks J,Sako D,Wiswall E,Xu J,Szklut P,Patel VS

doi

10.1007/s11095-006-9018-1

subject

Has Abstract

pub_date

2006-08-01 00:00:00

pages

1743-9

issue

8

eissn

0724-8741

issn

1573-904X

journal_volume

23

pub_type

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