Anticoagulant activity of Hirulog, a direct thrombin inhibitor, in humans.
Hirulog (BG8967) is a direct thrombin inhibitor built by rational design using the protein hirudin as a model (Maraganore et al. [1990]; Biochemistry 29: 7095-101). In order to evaluate the therapeutic potential for hirulog in the management of thrombotic disease, the tolerability and anticoagulant activity of the agent were examined in a study of human volunteers. In a randomized, placebo-controlled study (n = .54), the intravenous infusion of hirulog over 15 min showed a rapid, dose-dependent prolongation of activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT). There was a corresponding dose-dependent increase in plasma hirulog levels. The peptide was rapidly cleared with a half-life of 36 min and a total body clearance rate for the peptide of 0.43 l kg-1 h-1. Similar activity was observed following subcutaneous injection but with sustained pharmacodynamic and pharmacokinetic behavior. There was a significant correlation between pharmacokinetic and pharmacodynamic variables for both intravenous (r = 0.8, p < 0.001) and subcutaneous administration (r = 0.7, p = 0.002). To evaluate the possible interactions of aspirin on the tolerability and anticoagulant activity of intravenous hirulog, a cross-over design was employed in eight subjects. Aspirin administration did not modify the peptide's activity. At the administered dose of 0.6 mg kg-1 h-1 for 2 h, hirulog infusion prolonged APTT from 230 to 260% baseline. The infusion of hirulog in subjects who had received aspirin was not associated with any significant changes in the template bleeding time.(ABSTRACT TRUNCATED AT 250 WORDS)
Fox
I
I
Department Biogen, Inc., Cambridge, MA 02142.
Dawson
A
A
Loynds
P
P
Eisner
J
J
Findlen
K
K
Levin
E
E
Hanson
D
D
Mant
T
T
Wagner
J
J
Maraganore
J
J
D000293:Adolescent; D000328:Adult; D000925:Anticoagulants / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation; D004361:Drug Tolerance; D006487:Hemostasis / Q000187:drug effects; D006629:Hirudins / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D013917:Thrombin / Q000037:antagonists & inhibitors*
D000925:Anticoagulants; D006629:Hirudins; D010446:Peptide Fragments; D011994:Recombinant Proteins; D013917:Thrombin; D001241:Aspirin; C074619:bivalirudin