A Phase I Double-Blind, Ascending Dose Study of an Oral Synthetic Direct Thrombin Inhibitor, TGN167.

Background: TGN167 is a potent (Ki = 7-22nM), reversible, low molecular weight, and highly selective synthetic direct thrombin inhibitor. The aim of study was to evaluate the pharmacokinetics, pharmacodynamics and safety of TGN167. TGN167 tablets were administered via the oral route to 20 healthy male subjects as single doses in a randomised double blind placebo controlled study, upward titration of up to four dosage levels.

Methods: The group consisted of 20 healthy male volunteers, 18 of whom received active compound and two of whom received placebo in each arm of the study. Within the group receiving active compound, 9 were randomised to receive an enteric coated presentation and nine to receive a non-enteric coated presentation. Orally administered doses were: 75mg (one tablet), 150mg (two tablets), 300mg (four tablets) and 600 mg (eight tablets). The interval between each dose of TGN167 was one week minimum. The allocation of the placebo was such that each volunteer would only receive placebo once during the course of the study. Plasma concentration of TGN167 was evaluated through a validated LC-MS/MS method. Pharmacodynamic activity was assessed through measurement of the thrombin clotting time (TT) and activated Partial Thromboplastin Time (aPTT).

Results: Variability of each PK parameter was systematically lower for non-enteric than enteric. The non-enteric coated formulation exhibited lower inter-subject variability. Both Cmax and AUC increased in a dose proportional way. Oral administration of TGN167 induced a dose-related increase in the TT, reaching a peak within 2 to 3h after administration, with maximum mean values being approximately 2.5 to 7 fold higher than at pre-dose. A fall in TT to 1.5 fold baseline values occurred within 4 and 8 hours after administration (for the non-enteric and enteric formulations respectively). All TT had returned to baseline 10 and 12 hours after administration (for non-enteric and enteric formulations respectively). Of note, in the highest dose group (600mg), TT value was uncoagulable at one or 2 time points (1, 2, 3 h after oral administration) in 7 subjects/15. The effect of TGN167 on aPTT was less marked and of a shorter duration. The maximum mean values were 2 fold baseline, observed 2 h after oral administration of the non-enteric formulation, and 4 to 6 h after oral administration of the enteric coated formulation. Thereafter, mean values declined to pre-dose values by approximately 8 to 10h after administration (non-enteric) and 8 to 12h post administration (enteric coated). The high TT/aPTT index offered by TGN167 is clearly displayed in the 7 subjects in whom the TT was raised to 180 seconds (assay saturation) and whose aPTT remained below 2 fold baseline. No clinically significant findings were detected in any safety assessments. There were no adverse clinical events of either a general or cardiovascular nature (including liver function tests and ECG changes) during the study period of 24 hours for any dose of TGN167.

Conclusion: The above results indicate that TGN 167 has the desired properties of an oral antithrombotic drug, including a stable pharmacokinetic profile with marked potentiation of TT and minimal effects on aPTT.