Pharmacokinetics and pharmacodynamics of sibrafiban alone or in combination with ticlopidine and aspirin

Aims The purpose of this clinical study was to evaluate the effects of a ti clopidine/aspirin combination on the pharmacokinetics and pharmacodynamics of sibrafiban and the tolerability of the combination therapy Methods Thirty-eight healthy male volunteers were randomized to receive one of the following treatments for 7 days: sibrafiban (n = 12), ticlopidine/a spirin (n = 12), or the combination treatment sibrafiban/ticlopidine/aspiri n (n = 14). Concentrations of the active metabolite of sibrafiban, Ro 44-38 88, in plasma and urine were determined by column-switching liquid chromato graphy combined with tandem mass spectrometry. The pharmacodynamics of sibr afiban and ticlopidine/aspirin were examined by measuring the inhibition of ADP- or collagen-induced platelet aggregation. Results The addition of ticlopidine/aspirin to sibrafiban did not significa ntly alter the pharmacokinetic parameters of Ro 44-3888. the geometric mean ratio for AUC(0,12h) was 110 (95% CI 0.82, 1.22). Separately, sibrafiban a nd ticlopidine/aspirin inhibited ADP-and collagen-induced platelet aggregat ion and the effects of the two treatments were additive. For example, the a verage inhibition of ADP-induced platelet aggregation over 12 h was 42% in the sibrafiban treated group, 55% in the ticlopidine/aspirin group and 69% in the sibrafiban/ticlopidine group. The bleeding time was prolonged in the treatments with ticlopidine/aspirin (8.1 min) and sibrafiban/ticlopidine/a spirin (8.6 min) compared with sibrafiban alone (3.5 min). Conclusions This study shows a significant pharmacodynamic interaction betw een sibrafiban and ticlopidine/aspirin. Consequently, the simultaneous admi nistration of sibrafiban and ticlopidine/aspirin should be carefully monito red to ensure the patient's coverage with an antiplatelet drug without expo sure to an excessive bleeding risk.