Effect on Absolute Prothrombin Time

Prothrombin time data obtained using rabbit brain thromboplastin with the three increasing ISI values during these ex vivo studies are presented in Table 1. The source and sensitivity of thromboplastin used in the assay affected the absolute PT value in all species, clearly demonstrating the need to standardize this reagent in preclinical assessment and to be cognizant of this impact in clinical trials or postmarketing, when reagents are less likely to be standardized. As anticipated, addition of the FXa inhibitor to plasma under ex vivo conditions increased the PT in a dose-dependent manner. This increase in PT time length was observed regardless of the ISI value (sensitivity) of the throm-boplastin used and occurred in all species (Table 1). Although the absolute time for clot formation generally increased with increasing ISI, this was not true for all assessments.

Table 2 summarizes the maximum change in PT and the range of variability when rabbit brain thromboplastin of varying ISI values was compared to human recombinant thromboplastin. Again, in general, the higher the PT value, the larger the deviation between reagent types. For example, although there was a 2.1-second difference between human and rabbit thromboplastin in untreated human plasma, the difference increased from 5.5, 9.2, 12.0, 13.6, and 38.2 seconds in samples containing 0.2, 0.6, 1.2, 1.8, or 6.0|g/mL FXa inhibitor, respectively. Dogs were much less sensitive to the type of thrombo-

TABLE 1 In Vitro Effect of an Experimental Factor Xa Inhibitor on Absolute Prothrombin Time Using a Rabbit Brain Thomboplastin

_ _ International Sensitivity Index" Concentration of Factor ___

TABLE 1 In Vitro Effect of an Experimental Factor Xa Inhibitor on Absolute Prothrombin Time Using a Rabbit Brain Thomboplastin

_ _ International Sensitivity Index" Concentration of Factor ___

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