Drotrecogin alfa

Drotrecogin alfa is a recombinant version of the natural plasma-derived activated Protein C, from which it differs only by unique oligosaccharides in the carbohydrate portion of the molecule. Activated Protein C is a crucial coagulation regulator. It limits thrombin formation by inactivating factors Va and VIIIa, thereby providing negative feedback regulation of coagulation. Excessive coagulation activation in the microcirculatory bed plays a significant part in the pathophysiology of severe sepsis. Furthermore, Activated Protein C is an important modulator of the systemic response to infection and has antithrombotic and profibrinolytic properties. Drotrecogin alfa has similar properties to those of endogenous human Activated Protein C.

Pharmacodynamic Effects

In placebo-controlled clinical trials in patients with severe sepsis, drotrecogin alfa exerted an antithrombotic effect by limiting thrombin generation and improved sepsis-associated coagulopathy, as shown by a more rapid improvement in markers of coagulation and fibrinolysis. Drotrecogin alfa caused a more rapid decline in thrombotic markers such as D-dimer, prothrombin F1.2, and thrombin-antithrombin levels and a more rapid increase in Protein C and antithrombin levels. Drotrecogin alfa also restored endogenous fibrinolytic potential, as evidenced by a more rapid trend toward normalisation in plasminogen levels and a more rapid decline in plasminogen activator inhibitor-1 levels. Additionally, patients with severe sepsis treated with drotrecogin alfa had a more rapid decline in interleukin-6 levels, a global marker of inflammation, consistent with a reduction in the inflammatory response.

Drotrecogin alfa (activated) and endogenous human Activated Protein C are inactivated in plasma by endogenous protease inhibitors but the mechanism by which they are cleared from plasma is unknown. Plasma concentrations of endogenous Activated Protein C in healthy subjects and patients with severe sepsis are usually below detection limits (<5 ng/ml) and do not significantly influence the pharmacokinetic properties of drotrecogin alfa (activated).

In healthy subjects, greater than 90% of the steady state condition is attained within 2 hours following the start of a constant-rate intravenous infusion of drotrecogin alfa. Following the completion of an infusion, the decline in plasma drotrecogin alfa (activated) concentrations is biphasic and is comprised of a rapid initial phase (t_½α=13 minutes) and a slower second phase (t_½β=1.6 hours). The short half-life of 13 minutes accounts for approximately 80% of the area under the plasma concentration curve and governs the initial rapid accrual of plasma drotrecogin alfa (activated) concentrations towards the steady-state. Plasma drotrecogin alfa (activated) steady-state concentrations are proportional to the infusion rate over a range of infusion rates from 12 μg/kg/hr to 48 μg/kg/hr. The mean steady-state plasma concentration of drotrecogin alfa (activated) in healthy subjects receiving 24 μg/kg/hr is 72 ng/ml.

In patients with severe sepsis, infusion of drotrecogin alfa (activated) from 12 μg/kg/hr to 30 μg/kg/hr rapidly produced steady-state plasma concentrations that were proportional to infusion rates. In the Phase 3 trial, the pharmacokinetics of drotrecogin alfa (activated) were evaluated in 342 patients with severe sepsis administered a 96-hour continuous infusion at 24 μg/kg/hr. The pharmacokinetics of drotrecogin alfa (activated) were characterised by attainment of steady-state plasma concentration within 2 hours following the start of the infusion. In the majority of patients, measurements of Activated Protein C beyond 2 hours after termination of the infusion were below the quantifiable limit, suggesting rapid elimination of drotrecogin alfa (activated) from the systemic circulation. The plasma clearance of drotrecogin alfa (activated) is approximately 41.8 l/hr in sepsis patients as compared with 28.1 l/hr in healthy subjects.

In patients with severe sepsis, the plasma clearance of drotrecogin alfa (activated) was significantly decreased by renal impairment and hepatic dysfunction, but the magnitude of the differences in clearance (<30%) does not warrant any dosage adjustment.

Changes observed in monkeys at, or in small excess of, the maximum human exposure during repeated dose studies, were all related to the pharmacological effect of drotrecogin alfa and include beside the expected prolongation of APTT, decreases in haemoglobin, erythrocytes and haematocrit, and increases in reticulocyte count and PT.

Drotrecogin alfa (activated) was not mutagenic in an in vivo micronucleus study in mice or in an in vitro chromosomal aberration study in human peripheral blood lymphocytes with or without rat liver metabolic activation.

Carcinogenicity studies and animal reproduction studies have not been conducted with drotrecogin alfa. However, with respect to the latter, the potential risk for humans being unknown, drotrecogin alfa should not be used during pregnancy unless clearly necessary.