Classical anticoagulants like warfarin and heparin have their problems: there are issues with dosing, interactions with other drugs and even foodstuffs, and it can be a challenge to maintain effective, safe blood thinning when required.
This is a particular issue with deep vein thrombosis prophylaxis during surgery, and clots that can lead to stroke are also common in patients with atrial fibrillation. So better, safer, more predictable anticoagulants would be of great benefit.
There are several points along the clotting cascade that could be targets for anticoagulants. One drug that acts as an inhibitor of Factor Xa, the serine protease that converts prothrombin to thrombin, has already been approved – Bayer’s rivaroxaban. Another, edoxaban, is being developed by Daiichi Sankyo, and is showing promise in clinical trials.1
In one single blind, placebo-controlled, randomised, two-part study, 85 healthy subjects were given single ascending doses of 10 to 150mg, and a further 36 given 90mg or 120mg once a day, or 60mg twice a day.2 The effects of food and tablet versus solution formulation were also assessed in a crossover study. Single doses of up to 150mg were well tolerated, and in the multiple dose study, mean accumulation showed an elimination half-life of between 9 and 10 hours. It was safe and well tolerated in all doses.
A Phase II trial has also taken place. A total of 903 patients undergoing total hip replacement were given oral doses of 15, 30, 60 or 90mg of the drug or subcutaneous dalteparin once a day, beginning 6–8 hour post-operation.3 A total of 776 subjects were evaluable, and there was a statistically significantly lower incidence of venous thromboembolism in the edoxaban group – 28% for the lowest dose and 11% for the highest dose, compared with 44% for the control dalteparin group. The incidence of clinically relevant bleeding was low and similar for all patients.
Further trials are under way in both venous thromboembolism and atrial fibrillation.
references
1. T. Nagata et al. Bioorg. Med. Chem. 2009, 17, 1193
2. K. Ogata et al. J. Clin. Pharmacol. 2010, 50, 743
3. G. Raskob et al. Thromb. Haemost. 2010, Jun, epub ahead of print
