The early phase development of drugs has entered into a new era and requires novel designs and rational choice of biomarkers. This is particularly true for drugs affecting the coagulation cascade. The most commonly used effect markers such as the activated partial thrombin time (aPTT) and the prothrombin (PT) were developed for the heparins and coumarins and these tests are hardly informative for compounds with a different pharmacology.

Summary

The effects of novel compounds such as selective and reversible inhibitors of coagulation factors are indeed not evaluated well with these tests and require adaptation of existing tests or the use of novel tests. The choice of tests is also important to allow frequent measurements and assess ‘on-line’ the level of anticoagulation and ensure subject safety because excess anticoagulation increases bleeding risk. Easy access to patients in which the results of the outcome of the first-in- human trials tests can be applied is important as well. Dose selection from the first studies facilitates a rapid transition of the proof of pharmacology to proof of concept. This can for instance be done by studying a relevant dose in ambulant or hospitalized patients.

Available tests

  • APTT, PT, ECT, PiCT, fibrinogen
  • Concentration of coagulation or fibrinolysis factors in quiescent or active form
  • TAT, D-dimer, prothrombin fragment 1+2, fibrinogen degradation products, PAP, plasminogen, PAP, etc.
  • Thrombin generation test – several variants
  • Whole blood platelet aggregometry using different inducers or combinations thereof
  • APC-PCI
  • Thromboelastometry
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