THE DOSE PROPORTIONALITY OF THE PHARMACOKINETICS OF ARDEPARIN, A LOW-MOLECULAR-WEIGHT HEPARIN, IN HEALTHY-VOLUNTEERS

Ardeparin is a low molecular weight heparin currently being evaluated as an antithrombotic agent. The objective of this investigation was to assess the effects of dose on the pharmacokinetics of ardeparin after subcutaneous administration. Eighteen healthy subjects received doses of 30 U/kg, 60 U/kg, and 100 U/kg antifactor Xa (aXa) of ardeparin by subcutaneous injection. Plasma antifactor IIa (aIIa) activity levels after the 30- and 60-U/kg doses of ardeparin were too low to reliably characterize the disposition of the drug. However, the pharmacokinetic s of ardeparin could be characterized by using pharmacodynamic measure ments of plasma aXa activity. The rate of absorption of ardeparin afte r subcutaneous administration did not change with increasing dose. The volume of distribution (Vd) of ardeparin was small, reflecting minima l distribution outside the intravascular space, and was independent of dose. The total clearance of ardeparin, however, decreased with incre asing dose, and half-life (t(1/2)) was prolonged at the higher doses. Within the observed dose range, a doubling of the ardeparin dose resul ted in on area under the plasma aXa activity-versus-time curve (AUC) t hat was approximately 25% greater than expected on the basis of linear disposition, The differences in AUC and clearance between the three d oses suggest that the mechanism of elimination of ardeparin is saturab le.