General Pharmacology

Activated Protein C exerts an antithrombotic effect by inhibiting Factors Va and VIIIa. In vitro data indicate that Activated Protein C may have indirect profibrinolytic activity through its ability to inhibit plasminogen activator inhibitor-1 (PAI-1) and may exert an anti-inflammatory effect by limiting the chemotactic response of leukocytes to inflammatory cytokines, an inhibitory process mediated by leukocyte cell surface Activated Protein C receptor. In addition, in vivo data suggest Activated Protein C may reduce interactions between leukocytes and the microvascular endothelium. In vitro bacterial phagocytosis by neutrophils and monocytes is not affected.

Pharmacodynamics

The specific mechanisms by which Xigris exerts its effect on survival in patients with severe sepsis are not completely understood. In patients with severe sepsis, Xigris infusions of 48 or 96 hours produced dose-dependent declines in D-dimer and IL-6. Compared with placebo, Xigris-treated patients experienced more rapid declines in D-dimer, PAI-1 levels, thrombin-antithrombin levels, prothrombin F1.2, IL-6, more rapid increases in protein C and antithrombin levels, and normalization of plasminogen. As assessed by infusion duration, the maximum observed pharmacodynamic effect of drotrecogin alfa (activated) on D-dimer levels occurred at the end of 96 hours of infusion for the 24 mcg/kg/hr treatment group.

Human Pharmacokinetics

Xigris and endogenous Activated Protein C are inactivated by endogenous plasma protease inhibitors. Plasma concentrations of endogenous Activated Protein C in healthy subjects and patients with severe sepsis are usually below detection limits.

In patients with severe sepsis, Xigris infusions of 12 mcg/kg/hr to 30 mcg/kg/hr rapidly produce steady-state concentrations (Css) that are proportional to infusion rates. In Study 1 (see Clinical Studies), the median clearance of Xigris was 40 L/hr (interquartile range of 27 to 52 L/hr). The median C_ss of 45 ng/mL (interquartile range of 35 to 62 ng/mL) was attained within 2 hours after starting infusion. In the majority of patients, plasma concentrations of Xigris fell below the assay's quantitation limit of 10 ng/mL within 2 hours after stopping infusion. Plasma clearance of Xigris in patients with severe sepsis is approximately 50% higher than that in healthy subjects.

Special Populations

In adult patients with severe sepsis, small differences were detected in the plasma clearance of Xigris with regard to age, gender, hepatic dysfunction, renal dysfunction, or obesity. Dose adjustment is not required based on these factors alone or in combination (see WARNINGS and PRECAUTIONS).

End Stage Renal Disease - Patients with end stage renal disease requiring chronic renal replacement therapy were excluded from Study 1. In patients without sepsis undergoing hemodialysis (n=6), plasma clearance (mean ± SD) of Xigris administered on non-dialysis days was 30 ± 8 L/hr. Plasma clearance of Xigris was 23 ± 4 L/hr in patients without sepsis undergoing peritoneal dialysis (n=5). These clearance rates did not meaningfully differ from those in normal healthy subjects (28 ± 9 L/hr) (n=190).

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