Pharmacokinetics and pharmacodynamics of BIBT 986, a novel small molecule dual inhibitor of thrombin and factor Xa.
BACKGROUND
Current anticoagulant development focuses on agents with predictable pharmacokinetic and pharmacodynamic (PD) properties. BIBT 986 is a novel potent anticoagulant with a dual mechanism of action: it competitively inhibits factor (F) Xa and FIIa.


OBJECTIVE
To determine the safety, tolerability, pharmacokinetics (PK) and PD of BIBT 986 following intravenous infusion in healthy male volunteers.


METHODS
In three randomized, double-blind, placebo-controlled trials, subjects were administered by intravenous infusion escalating doses of BIBT 986 for up to 32 h. BIBT 986 concentrations were determined in plasma and urine samples by high pressure liquid chromatography tandem mass spectrometry. Pharmacodynamic response was assessed by measuring the changes in blood coagulation times. Activated partial thromboplastin time, International Normalized Ratio, thrombin time and ecarin clotting time were determined and compared with baseline results.


RESULTS
In all three studies, intravenous infusion of BIBT 986 was safe and well tolerated. BIBT 986 exhibited linear PK over the dose range tested. Clearance was about 8 L h(-1) and V(ss) about 50 L. Apparent steady state concentrations were reached within 24 h, indicating a dominant half-life of about 6 h. The terminal half-life of BIBT 986 was approximately 12 h. Renal excretion contributes approximately 50% to total elimination. Overall interindividual variability in pharmacokinetic and PD parameters was < 40%. There was a linear correlation between plasma concentrations and PD responses, suggesting excellent predictability.


CONCLUSIONS
BIBT 986 is the first small molecule of a novel class of anticoagulants that potently and directly inhibits both coagulation FXa and thrombin. It has predictable pharmacokinetic and PD characteristics.
Graefe-Mody
E U
EU
Department of Clinical Pharmacology, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria.
Schühly
U
U
Rathgen
K
K
Stähle
H
H
Leitner
J M
JM
Jilma
B
B
D000293:Adolescent; D000328:Adult; D000925:Anticoagulants / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D001780:Blood Coagulation Tests; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D015951:Factor Xa / Q000008:administration & dosage / Q000494:pharmacology; D065427:Factor Xa Inhibitors; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D010599:Pharmacokinetics; D015203:Reproducibility of Results; D013917:Thrombin / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000494:pharmacology
D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D013917:Thrombin; D015951:Factor Xa