Disposition of a novel recombinant antithrombotic agent, RG 12986, in cynomolgus monkeys

RG 12986, a novel antagonist of platelet aggregation, is a recombinant peptide based on the sequence in von Willebrand factor, which contains the GP1b binding site. Disposition of the peptide in cynomolgus monkeys was determined using nonlabeled and 35S-labeled product. After iv administration, the peptide underwent a triphasic decay in the plasma. The first phase of elimination, after distribution, had a t1/2 (approximately 20 min) similar to that observed for inhibition of platelet aggregation (approximately 25 min). The correlation between the logarithm of the plasma peptide concentration and activity was r = 0.9989. The effective duration of pharmacological activity was approximately 2 hr. After this period, a slower terminal phase of plasma elimination was observed (t1/2 approximately 2 hr). Plasma clearance (7-15 ml/min/kg) and volume of distribution at steady-state (0.4-0.9 L/kg) estimates appeared to have a slight dose dependency, but the scope of the investigation did not allow this to be verified. There was a linear correlation between dose and AUC (r2 = 0.9998), but for each 4-fold increase in dose there was a greater than 4-fold increase in AUC. Immediately after iv administration, significant fragmentation of the peptide was observed with polyacrylamide gel electrophoresis analysis of the plasma. This initial rate of metabolism was subsequently slowed to t1/2 estimates of 2 hr, followed by a very long terminal half-life of plasma radioactivity of 12 days. It is likely that this terminal half-life represents metabolic recycling of 35S. Elimination of the label was primarily via the kidneys.