Extending the role of antithrombotic agents: an example based on the low-molecular-weight heparin, tinzaparin.
We illustrate a strategy for developing an antithrombotic agent based on the low-molecular-weight heparin (LMWH) tinzaparin experience. After anti-factor Xa and IIa activity pharmacokinetic characterization in healthy volunteers, clinical studies first explored the doses and then confirmed thrombosis prevention effects in postoperative (general and hip or knee replacement surgery) settings as compared with placebo and active treatments. This experience and additional dose-finding assessments led to large clinical studies verifying the effectiveness of tinzaparin in the treatment of deep vein thrombosis and acute pulmonary embolism. Subgroup analyses from these studies and preclinical experiments suggested a role for tinzaparin in patients with malignancy who are at high risk for thromboembolic complications. Challenging patient populations and other thrombotic disorders spawned interest in tinzaparin studies in the obese, the hemodialysis, the stroke, peripheral angioplasty, and the pregnant patient as well as in children with thromboembolic disorders. New therapeutic challenges were addressed with a bridging study for patients requiring interruption of oral anticoagulant therapy, a study of patients undergoing cardioversion for atrial fibrillation, and outpatient venous thromboembolism treatment studies. Efficient antithrombotic development programs not only build on traditional indications but elaborate on new therapeutic hypotheses generated from clinical studies, new therapeutic areas, and on-going basic science research programs.
Hainer
James W
JW
Astra Zeneca, Wilmington, Delaware 19850, USA. james.hainer@astrazeneca.com
Sprogel
Per
P
Lindenstroem
Ewa
E
D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D006495:Heparin, Low-Molecular-Weight / Q000627:therapeutic use*; D006801:Humans; D009369:Neoplasms / Q000150:complications / Q000188:drug therapy; D013927:Thrombosis / Q000188:drug therapy / Q000517:prevention & control; D000078222:Tinzaparin
D005343:Fibrinolytic Agents; D006495:Heparin, Low-Molecular-Weight; D000078222:Tinzaparin