Pharmacokinetics and pharmacodynamics of terbogrel, a combined thromboxane A2 receptor and synthase inhibitor, in healthy subjects.
OBJECTIVE
To characterize the pharmacokinetics of terbogrel, a new combined thromboxane A2 (TxA2) 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 TxA2 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 TxA2 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.
Guth
Brian D
BD
Department of Drug Discovery Support, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65, Postfach 1755, 88397 Biberach an der Riss, Germany. brian.guth@bc.boehringer-ingelheim.com
Narjes
Hans
H
Schubert
Hans-Dieter
HD
Tanswell
Paul
P
Riedel
Axel
A
Nehmiz
Gerhard
G
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000328:Adult; D001241:Aspirin / Q000008:administration & dosage; D001760:Bleeding Time; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006801:Humans; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D011725:Pyridines / Q000493:pharmacokinetics* / Q000494:pharmacology; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D011725:Pyridines; D013928:Thromboxane A2; D015121:6-Ketoprostaglandin F1 alpha; C112331:terbogrel; D013930:Thromboxane-A Synthase; D001241:Aspirin