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Pharmacokinetics and Pharmacodynamics of Sibrafiban, an Orally Administered IIb/IIIa Antagonist, in Patients with Acute Coronary Syndrome
Author(s) -
Modi Nishit B.,
Novotny William,
Reimann James D.,
Can Christopher P.,
Braunwauld Eugene
Publication year - 1999
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/00912709922008317
Subject(s) - pharmacokinetics , prodrug , dosing , pharmacodynamics , pharmacology , active metabolite , medicine , oral administration , trough concentration
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 .