The BBC has reported on calls for the new blood-thinning drug Pradaxa (dabigatran etexilate/BIBR 1048) to be used more widely in patients who are at risk of blood clots following surgery, a serious complication that kills 25,000 patients each year. This drug works be inhibiting the enzyme Thrombin, a key player in clot formation.
Clinical trials indicate that thew new drug is as effective at preventing clotting as existing treatments, but that it is easier to get the dose right and that overall it is significantly safer. Another advantage is that it is taken as a pill rather than requiring daily injections, such injections are often painful and can lead patients to stop taking anticoagulant drugs such as heparin. Several large scale trials of Pradaxa are underway, and it is undergoing assessment by the UK’s National Institute for Health and Clinical Excellence, although it has already been licensed for patients undergoing knee and hip operations on the NHS.
We hope that the larger trials go well and that this drug is approved for use by NICE. In the meanwhile it’s worthwhile to take a look at the contribution made by animal research to its development, and the role of animals alongside other computational, chemical and in vitro methods.
As is usual the early design of this drug relied on computer aided analysis of the structure of thrombin and in vitro studies using human thrombin (1). This analysis yielded a number of candidate molecules which were assessed for their ability to inhibit thrombin in rats and rabbits, and eventually one was identified that combined a potent ability to inhibit thrombin with low toxicity, even at high doses. Unfortunately this molecule was not active when given orally, it needed to be injected, so it was further modified in an attempt to make a drug that could be given in pill form. Several candidate drugs were assessed in rabbits and subsequently in monkeys and one, BIBR 1048, was found to have very good anticoagulant activity when given orally (1). On the basis of these results, and of course additional regulatory toxicity tests, BIBR 1048 was selected to go into clinical trials.
1) Hauel N.H. et al. “Structure-based design of novel potent nonpeptide thrombin inhibitors.” J Med Chem. Volume 45, Issue 9, Pages 1757-66 (2002) PubMed: 11960487.