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Pharmacokinetics and pharmacodynamics of terbogrel, a combined thromboxane A 2 receptor and synthase inhibitor, in healthy subjects
Author(s) -
Guth Brian D.,
Narjes Hans,
Schubert HansDieter,
Tanswell Paul,
Riedel Axel,
Nehmiz Gerhard
Publication year - 2004
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2004.02083.x
Subject(s) - thromboxane a synthase , pharmacology , pharmacokinetics , thromboxane a2 , prostacyclin , pharmacodynamics , thromboxane , antithrombotic , thromboxane receptor , medicine , oral administration , chemistry , receptor , endocrinology , platelet
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 I C 50 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.