Background: Dabigatran etexilate (BIBR 1048) is definitely an dental direct thrombin inhibitor undergoing evaluation to prevent venous thromboembolism (VTE) following total hip substitute. Following dental administration, dabigatran etexilate is quickly transformed into its active form dabigatran (BIBR 953 ZW).

Objectives: To look for the safe therapeutic selection of dabigatran etexilate following total hip substitute.

Methods: Inside a multicenter, open-label, dose-escalating study, 314 patients received dental doses of dabigatran etexilate (12.5, 25, 50, 100, 150, 200 and 300 mg two times daily or 150 and 300 mg once daily) administered 4-8 h after surgery, for six-ten days. Dose escalation took it’s origin from clinical and pharmacokinetic data. The main safety effects were major bleeding. The main effectiveness outcome incorporated venographic deep vein thrombosis (DVT), symptomatic DVT and lung embolism, throughout the treatment period.

Results: No major bleeding event was noticed in any group, but two patients in the greatest dose (300 mg two times daily) endured bleeding from multiple sites connected with reduced kidney clearance and prolonged pharmacodynamic (PD) parameters. A serving-response was shown for minor bleeding occasions. From the 289 treated patients, 225 patients had evaluable venograms. The general incidence of DVT was 12.4% (28/225 patients). There wasn’t any consistent relationship between your dose and incidence of DVT, the greatest incidence in almost any group being 20.8% (5/24 patients). The cheapest dose (12.5 mg two times daily) demonstrated maximum proximal DVT [12.5% (3/24)] with no rise in PD parameters. Peak and trough plasma concentrations, area underneath the dabigatran plasma concentration-time curve and PD parameters also elevated compared using the dose. Greater dabigatran plasma concentrations were connected with lower DVT rates. Roughly 20% of the sufferers had low plasma concentrations following the first dose suggesting further optimization from the preliminary tablet formulation is needed.BIBR 953

Conclusions: Dabigatran etexilate demonstrates a suitable safety profile, having a therapeutic window above 12.5 mg and below 300 mg two times daily. The reduced quantity of VTE occasions within each treatment group signifies a acceptable antithrombotic potential, even though the study wasn’t powered to have an effectiveness analysis. Additional research is ongoing to optimize dental absorption and also the effectiveness/safety balance.