Clinical pharmacology of intravenously administered recombinant desulfatohirudin (CGP 39393) in healthy volunteers.
Clinical pharmacology of the intravenously administered recombinant desulfatohirudin CGP 39393 was investigated in 47 healthy volunteers in a multicenter study. Mean peak concentrations after bolus injections of 0.1, 0.3, 0.5, and 1.0 mg/kg were 154, 443, 764, and 1,691 nmol/L, respectively. Intravenous infusions of 0.1 mg/kg/h for 6 h and of 0.2 and 0.3 mg/kg/h for 6 h and 72 h resulted in mean steady-state levels of 78, 227, and 312 nmol/L. Elimination was multiexponential and dose independent. Concordant pharmacokinetic parameters were obtained from both i.v. bolus and infusion experiments (overall average total plasma clearance, 2.20 ml/min/kg; mean residence time, 2.12 h; volume at steady state, 0.27 L/kg). Thrombin inhibition by CGP 39393 was demonstrated ex vivo by the thrombin chromogenic assay (TCA), by activated partial thromboplastin time (APTT), thrombin time (TT), and prothrombin time (PT). Following a parabolic function APTT doubled and quadrupled at CGP 39393 concentrations of 100 and 1,000 nmol/L, respectively. Whereas TTs (bovine thrombin 3 or 6 IU/ml) were very sensitive to low CGP 39393 levels with unmeasurable clotting times at CGP 39393 concentrations greater than 30 and 60 nmol/L, PT was prolonged by a factor of only 1.3 above baseline at 300 nmol/L. APTT appears to be most suitable for monitoring the anticoagulant effect of CGP 39393 over a broad concentration range. The drug was well tolerated without clinically relevant bleeding episodes or other adverse events.
Marbet
G A
GA
Coagulation Laboratory, University Hospital Basel, Switzerland.
Verstraete
M
M
Kienast
J
J
Graf
P
P
Hoet
B
B
Tsakiris
D A
DA
Silling-Engelhardt
G
G
Close
P
P
D000328:Adult; D001760:Bleeding Time; D001777:Blood Coagulation / Q000187:drug effects*; D001792:Blood Platelets / Q000187:drug effects*; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D006629:Hirudins / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008297:Male; D010314:Partial Thromboplastin Time; D011517:Prothrombin Time; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D013918:Thrombin Time
D005343:Fibrinolytic Agents; D006629:Hirudins; D011994:Recombinant Proteins; C060225:desirudin