Pharmacokinetics and pharmacodynamics of sibrafiban, an orally administered IIb/IIIa antagonist, in patients with acute coronary syndrome.
Sibrafiban is a double prodrug that is converted to the inactive single prodrug and to the active IIb/IIIa antagonist following oral administration. Pharmacokinetics (PK) and pharmacodynamics (PD) of oral sibrafiban and its metabolites were evaluated in patients postacute coronary syndrome receiving once- or twice-daily sibrafiban for up to 28 days at several dose levels. Mean peak concentrations of sibrafiban were < 5 ng/mL. Peak single prodrug concentrations occurred 1.7 +/- 1.0 (mean +/- SD) hours after sibrafiban dosing. Total apparent plasma clearance of the single prodrug was 40 +/- 15 L/h, and the elimination half-life was 2.3 +/- 0.8 hours. Mean values of the steady-state pharmacokinetics for total concentrations of the active drug over all doses were: time to peak plasma concentration, 5.0 +/- 1.7 hours; apparent clearance, 13.9 +/- 3.9 L/h; and half-life, 11.0 +/- 2.8 hours. Once-daily dosing resulted in high peak-trough excursions in active drug concentrations: trough concentrations were 21% +/- 6% of peak. Twice-daily dosing resulted in an AUC for the active drug on Day 28 that was 168% +/- 36% of that on Day 1, and steady-state trough concentrations were 54% +/- 10% of peak with sustained inhibition of platelet aggregation. Dose-adjusted steady-state active drug concentrations increased with increasing age and with decreasing renal function and body weight.
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Department of Pharmacokinetics, Genetech, Inc., South San Francisco, CA, USA.
Novotny
W
W
Reimann
J D
JD
Cannon
C P
CP
Braunwauld
E
E
D000208:Acute Disease; D000284:Administration, Oral; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000578:Amidines / Q000097:blood / Q000652:urine; D019540:Area Under Curve; D001835:Body Weight; D003327:Coronary Disease / Q000188:drug therapy* / Q000378:metabolism; D004311:Double-Blind Method; D005260:Female; D005919:Glomerular Filtration Rate; D006571:Heterocyclic Compounds / Q000097:blood / Q000652:urine; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D010091:Oximes / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D010880:Piperidines / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D010975:Platelet Aggregation Inhibitors / Q000493:pharmacokinetics*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D011355:Prodrugs / Q000493:pharmacokinetics*; D013577:Syndrome
D000578:Amidines; D006571:Heterocyclic Compounds; D010091:Oximes; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011355:Prodrugs; C100916:Ro 44-3888; C110992:Ro 48-3656; C100917:sibrafiban