Pharmacokinetics and pharmacodynamics of terbogrel, a combined thromboxane A2 receptor and synthase inhibitor, in healthy subjects

Aims To characterize the pharmacokinetics of terbogrel, a new combined thromboxane A(2) (TxA(2)) receptor and synthase inhibitor, in healthy human subjects after single or multiple oral administration. Methods Forty-eight healthy male subjects received a single oral dose (10, 25, 50, 100, 150 or 200 mg) of terbogrel or placebo and 32 different subjects received one of the following treatments twice daily for 7 days: 50, 100 or 150 mg terbogrel, placebo, or once-a-day 330 mg acetylsalicylic acid. Results Terbogrel was well tolerated without obvious adverse effects following either a single oral dose or administration over 7 days. Plasma drug concentrations were dose-linear and there was no accumulation over 7 days. There was a dose-dependent blockade of TxA(2) receptors and of inhibition of thromboxane synthase activity with values for IC50 of 12 ng ml(-1) and 6.7 ng ml(-1), respectively. At the highest dose tested (150 mg) there was almost complete inhibition of thomboxane synthase and thromboxane receptor occupancy. Even at trough concentrations, receptor occupancy remained above 80% and thromboxane synthase was still completely inhibited. These two activities were associated with a dose-dependent inhibition of platelet aggregation (>80% at the 150 mg dose of terbogrel) and enhanced prostacyclin production. Conclusions Terbogrel is a potent agent having two distinct, complimentary pharmacodynamic actions, namely inhibition of thromboxane synthase and antagonism of the TxA(2) receptor. The antithrombotic effect of terbogrel was dose-dependent and was associated with enhanced prostacyclin production. Terbogrel is an attractive candidate for long-term antithrombotic therapy.