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


CONCLUSIONS
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.
Wang
Qin
Q
Wyeth Research, 1 Burtt Road, Andover, Massachusetts 01810, USA. qwang@wyeth.com
Shorten
Douglas
D
Xu
Xin
X
Shaw
Gray D
GD
Schaub
Robert G
RG
Shea
Christopher
C
Brooks
Jonathan
J
Sako
Dianne
D
Wiswall
Erin
E
Xu
Jin
J
Szklut
Pamela
P
Patel
Vikram S
VS
D019943:Amino Acid Substitution; D000818:Animals; D004285:Dogs; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D007457:Iodine Radioisotopes; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D050506:Mutant Chimeric Proteins / Q000493:pharmacokinetics; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000493:pharmacokinetics*; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000493:pharmacokinetics; D014633:Valine / Q000502:physiology; D014841:von Willebrand Factor / Q000235:genetics / Q000502:physiology*
D007457:Iodine Radioisotopes; D050506:Mutant Chimeric Proteins; D019038:Platelet Glycoprotein GPIb-IX Complex; D011994:Recombinant Proteins; D014841:von Willebrand Factor; D014633:Valine