Recombinant human platelet glycoprotein Ibβ-immunoglobulin G1 chimeric proteins (GPIbβ-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 GPIbα-Ig chimeras, at certain position, increase the binding affinity to vWF over its “wild-type” GPIbα-Ig analog. The purpose of this study was to determine the pharmacokinetics of two valine substituted GPIbα-Ig chimeras, GPIbα-Ig/1V (valine substitution at 239 position) and GPIbα-Ig/2V (double valine substitution at 233 and 239 position), in mice, rats and dogs.Methods
Head-to-head comparisons of pharmacokinetics of GPIbα-Ig/1V and GPIbα-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 GPIbα-Ig/2V in rats were examined from the same blood samples for determination of matrix effect. The disposition of GPIbα-Ig/2V was also compared in vWF-deficient versus wild-type mice.Results
For GPIbα-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 GPIbα-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 GPIbα-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 GPIbα-Ig in laboratory animals are likely affected by their enhanced binding affinity for circulating vWF.