Key result
The combination of sibrafiban, ticlopidine, and aspirin did not alter sibrafiban pharmacokinetics (AUC ratio 110; 95% CI 0.82-1.22) but additively increased platelet inhibition to 69%.
Why the study?
Does the combination of sibrafiban with ticlopidine and aspirin alter pharmacokinetics and pharmacodynamics compared to either treatment alone in healthy male volunteers?
RCT (n=38)
randomized
Does the combination of sibrafiban with ticlopidine and aspirin alter pharmacokinetics and pharmacodynamics compared to either treatment alone in healthy male volunteers?
The combination of sibrafiban with ticlopidine and aspirin produces additive antiplatelet effects without altering sibrafiban pharmacokinetics, highlighting the need to monitor for excessive bleeding risk.
No pharmacokinetic interaction but additive platelet inhibition warrants bleeding monitoring in use; extends dual antiplatelet interaction data to healthy volunteers.
AIMS: The purpose of this clinical study was to evaluate the effects of a ticlopidine/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/aspirin (n = 12), or the combination treatment sibrafiban/ticlopidine/aspirin (n = 14). Concentrations of the active metabolite of sibrafiban, Ro 44-3888, in plasma and urine were determined by column-switching liquid chromatography combined with tandem mass spectrometry. The pharmacodynamics of sibrafiban 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 significantly 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 and ticlopidine/aspirin inhibited ADP-and collagen-induced platelet aggregation and the effects of the two treatments were additive. For example, the average 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/aspirin (8. 6 min) compared with sibrafiban alone (3.5 min). CONCLUSIONS: This study shows a significant pharmacodynamic interaction between sibrafiban and ticlopidine/aspirin. Consequently, the simultaneous administration of sibrafiban and ticlopidine/aspirin should be carefully monitored to ensure the patient's coverage with an antiplatelet drug without exposure to an excessive bleeding risk.
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Wittke et al. (2000) conducted an RCT in healthy male volunteers (n=38). sibrafiban/ticlopidine/aspirin vs. sibrafiban alone or ticlopidine/aspirin was evaluated on AUC(0,12h) of Ro 44-3888 (active metabolite of sibrafiban) (geometric mean ratio 110, 95% CI 0.82-1.22). The combination of sibrafiban, ticlopidine, and aspirin did not alter sibrafiban pharmacokinetics (AUC ratio 110; 95% CI 0.82-1.22) but additively increased platelet inhibition to 69%.
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