Low molecular weight heparins are often given because of their specific anti-factor Xa effect. Selective inhibition of factor Xa is an attractive target to limit the generation of thrombin. Factor Xa plays a fundamental role in the coagulation cascade; it is situated at the confluence of the intrinsic and extrinsic pathways. Inhibition of one molecule of factor Xa could be consistent with inhibition of 138 molecules of thrombin, thus preventing thrombosis much more than would mere neutralization of thrombin activity. DX-9065a is a low-molecular-weight compound that selectively and reversibly blocks activated factor X. The purpose of this study was to further characterize the pharmacokinetics, pharmacodynamics and safety profile of DX-9065a in an older population with known coronary artery disease (CAD). In addition, the study examined the relationship between DX-9065a and biochemical markers of coagulation.
The drug, DX, was administered as a bolus plus a constant infusion for 72 hours. Based on the kinetics of the drug, we expected a linear relationship between DX and anti-Xa activity early (at 4 hours, say). The relationship between the two may become non-linear after a longer period of time (say 72 hours). The drug may also have a small effect on INR, although there is less evidence for that. INR (International Normalized Ratio) is a measure of clotting time (anti-coagulation). A larger value means that a patient is more likely to bleed.
Power
The purpose of the trial was to estimate the dose response relationships. The calculation of sample size will be made according to the precision of our estimates of Area Under the Curve (AUC) for DX. Based on preliminary data, the mean AUC and standard deviation for a 10 mg dose was 1111 and 92.7 respectively. For a 20 mg dose, it was 2345 and 198.7, respectively. Concentration measurements are usually distributed as a lognormal distribution. The standard deviations for the logarithms were of 0.085 and 0.083 for the two dose levels. Note that the standard deviations of the logs are almost identical for the different doses even through the original standard deviations were very different. This further supports the use of the lognormal distribution. Thus the observations appear to be lognormally distributed with standard errors of about 8.5 percent (100 x .085). The trial was powered to distinguish a 10 percent change (from predicted) in mean AUC level. Based on a standard deviation of 8.5 percent, the power should be 81.7 percent to detect such a difference based on a sample size of 15 per arm.