Xigris mechanism



Keywords: xigris mechanism
Description: 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

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.

The specific pharmacologic effects by which Xigris (drotrecogin alfa) exerts its effect on survival in patients with severe sepsis are not completely understood. In patients with severe sepsis, Xigris (drotrecogin alfa) infusions of 48 or 96 hours produced dose-dependent declines in D-dimer and IL-6. Compared with placebo, Xigris (drotrecogin alfa) -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.

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

Patients with Renal Impairment — Patients with end stage renal disease requiring chronic renal replacement therapy were excluded from Study 1 [see Clinical Studies ]. In patients without sepsis undergoing hemodialysis (n=6), plasma clearance (mean ± SD) of drotrecogin alfa (activated) administered on non-dialysis days was 30 ± 8 L/hr. Plasma clearance of drotrecogin alfa (activated) 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). No dosage adjustment is necessary for patients with renal impairment requiring hemodialysis or peritoneal dialysis.

Other Subpopulations — In adult patients with severe sepsis, small differences were detected in the plasma clearance of drotrecogin alfa (activated) with regard to age, gender, hepatic impairment, and obesity. No dose adjustment is required based on these factors alone or in combination.

Prophylactic Heparin — In a randomized, double-blind, placebo-controlled trial in adult patients with severe sepsis (Study 4), coadministration of Xigris (drotrecogin alfa) (24 mcg/kg/hr for 96 hours) and prophylactic heparin (enoxaparin 40 mg every 24 hours or unfractionated sodium heparin 5000 U every 12 hours administered subcutaneously) did not alter the clearance and steady-state concentrations of drotrecogin alfa (activated). No dosage adjustment of Xigris (drotrecogin alfa) is recommended when coadministered with prophylactic heparin [see Clinical Studies ].

The efficacy of Xigris (drotrecogin alfa) was studied in an international, multi-center, randomized, double-blind, placebo-controlled trial (“PROWESS”) of 1690 patients with severe sepsis. Entry criteria included a systemic inflammatory response presumed due to infection and at least one associated acute organ dysfunction. Acute organ dysfunction was defined as one of the following: cardiovascular dysfunction (shock. hypotension. or the need for vasopressor support despite adequate fluid resuscitation); respiratory dysfunction (relative hypoxemia [PaO2 /FiO2 ratio < 250]); renal dysfunction (oliguria despite adequate fluid resuscitation); thrombocytopenia (platelet count < 80,000/mm 3 or 50% decrease from the highest value the previous 3 days); or metabolic acidosis with elevated lactic acid concentrations. Patients received a 96-hour infusion of Xigris (drotrecogin alfa) at 24 mcg/kg/hr or placebo starting within 48 hours after the onset of the first sepsis-induced organ dysfunction. The median duration of organ dysfunction prior to treatment was 18 hours, and 89% of patients received study drug within 24 hours after onset of the first organ dysfunction. Exclusion criteria encompassed patients at high risk for bleeding [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS ], patients who were not expected to survive for 28 days due to a preexisting, non-sepsis related medical condition, HIV-positive patients whose most recent CD4 count was ≤ 50/mm 3. patients on chronic dialysis, and patients who had undergone bone marrow. lung, liver. pancreas. or small bowel transplantation.

All-cause mortality was assessed 28 days after the start of study drug administration. Prospectively defined subsets for mortality analyses included groups defined by APACHE II score [see References ] (a score designed to assess risk of mortality based on acute physiology and chronic health evaluation), protein C activity, and the number of acute organ dysfunctions at baseline. The APACHE II score was calculated from physiologic and laboratory data obtained within the 24-hour period immediately preceding the start of study drug administration irrespective of the preceding length of stay in the intensive care unit.

The study was terminated after a planned interim analysis due to significantly lower mortality in patients on Xigris (drotrecogin alfa) than in patients on placebo. At 28 days, the overall mortality rates were 25% for the Xigris (drotrecogin alfa) -treated group and 31% for the placebo-treated group (p=0.005) (see Table 3 ).

Baseline APACHE II score was correlated with risk of death; among patients receiving placebo, those with the lowest APACHE II scores had a 12% mortality rate, while those in the 2nd, 3rd, and 4th APACHE quartiles had mortality rates of 26%, 36%, and 49%, respectively. The observed mortality difference between Xigris (drotrecogin alfa) and placebo was limited to the half of patients with higher risk of death, i.e. APACHE II score ≥ 25, the 3rd and 4th quartile APACHE II scores, where the 28-day mortality rates were 31% for the Xigris (drotrecogin alfa) -treated group and 44% for the placebo-treated group (p=0.0002) (see Table 3 ). The efficacy of Xigris (drotrecogin alfa) has not been established in patients with lower risk of death, e.g. APACHE II score < 25.

Table 3: 28-Day All-Cause Mortality for All Patients and for Subgroups Defined by APACHE II Score in Study 1






Photogallery Xigris mechanism:


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