New and Emerging Therapies for Sepsis

OBJECTIVE: To review the recent advances related to the pathophysiology of sepsis and the rationale for recombinant human-activated protein C (drotrecogin alfa) and other antisepsis agents currently in Phase III trials. DATA SOURCES: A MEDLINE (1990–December 2001) search was performed to identify pertinent literature on the pathophysiology of sepsis and treatment strategies. The search was supplemented with AdisInsight (Adis International) using the search terms sepsis, severe sepsis, or septic shock combined with agents in Phase II or higher clinical development. Abstracts presented at infectious diseases and critical care meetings were also reviewed. STUDY SELECTION AND DATA EXTRACTION: Clinical efficacy studies were selected for drotrecogin alfa and other Phase III investigational agents. DATA SYNTHESIS: Our current understanding of the pathophysiology of sepsis underscores the contribution of increased coagulation and diminished fibrinolytic activity working in conjunction with an excessive and dysregulated inflammatory response. The loss of homeostatic balance among these systems results in a systemic inflammatory response with generalized coagulopathy, microvascular thrombosis, and, ultimately, acute organ failure and death. As a result of these advances, several compounds are now in various phases of development. A recombinant human form of endogenous activated protein C (drotrecogin alfa) was recently approved by the Food and Drug Administration for severe sepsis in adults who have a high risk of death. It possesses anticoagulant, profibrinolytic, and antiinflammatory properties. Other compounds currently in Phase III trials include tissue-factor pathway inhibitor, tumor-necrosis factor antibody fragment, platelet-activating factor acetylhydrolase, antithrombin III, and pyridoxylated hemoglobin polyoxyethylene. CONCLUSIONS: With the recent approval of drotrecogin alfa, there is renewed optimism that we can effectively reduce sepsis-associated mortality.

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Guidance on patient Identification and Administration of Recombinant Human Activated protein C for the Treatment of Severe Sepsis

Canadian Journal of Infectious Diseases ◽

10.1155/2002/916317 ◽

2002 ◽

Vol 13 (6) ◽

pp. 361-372 ◽

Cited By ~ 6

Author(s):

Gary Garber ◽

RT Noel Gibney ◽

Bruce Light ◽

Claudio Martin ◽

Kenneth Cunningham ◽

...

Keyword(s):

Severe Sepsis ◽

Protein C ◽

Activated Protein C ◽

Phase Iii ◽

Number Needed To Treat ◽

Patient Identification ◽

Phase Iii Trial ◽

Risk Of Death ◽

Consensus Document ◽

Relative Risk Of Death

Approximately one-third of cases of severe sepsis result in death. Endogenous activated protein C (ApC) plays a key role in the regulation of the inflammation, fibrinolysis and coagulation associated with severe sepsis. In a recently published phase III trial, protein C Worldwide Evaluation in Severe Sepsis (pROWESS), intravenous administration of recombinant human ApC (rhApC) 24 µg/kg/h for 96 h to patients with severe sepsis resulted in a 6.1% reduction in absolute mortality and a 19.4% reduction in the relative risk of death from any cause within 28 days (number needed to treat = 16). This dose is now being applied in clinical practice.rhApC is recommended for the treatment of severe sepsis (sepsis associated with acute organ dysfunction) occurring as a result of all types of infection (Gram-negative bacterial, Gram-positive bacterial and fungal). A panel of Canadian clinicians experienced in the treatment of severe sepsis and the management of critical care patients has developed this consensus document to assist clinicians in appropriate patient selection and management of potential challenges associated with rhApC therapy.

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Obesity Does Not Alter the Pharmacokinetics of Drotrecogin Alfa (Activated) in Severe Sepsis

Annals of Pharmacotherapy ◽

10.1345/aph.1e386 ◽

2005 ◽

Vol 39 (2) ◽

pp. 262-267 ◽

Cited By ~ 18

Author(s):

Howard Levy ◽

David Small ◽

Darell E Heiselman ◽

Richard Riker ◽

Jay Steingrub ◽

...

Keyword(s):

Body Weight ◽

Severe Sepsis ◽

Actual Body ◽

Drotrecogin Alfa ◽

Phase Iii ◽

Actual Body Weight ◽

Open Label ◽

Risk Of Death ◽

Drotrecogin Alfa Activated ◽

Significant Difference

BACKGROUND: Drotrecogin alfa (activated) [DrotAA] is approved for the reduction of mortality in adults with severe sepsis (sepsis with acute organ dysfunction) and high risk of death. Patients whose actual body weight was >135 kg were excluded from the Phase III PROWESS trial. OBJECTIVE: To compare exposure to DrotAA in patients with severe sepsis weighing >135 kg with those weighing ⩽135 kg in an open-label, Phase IV trial, and quantify the elimination half-life (t1/2) of DrotAA in these patients. METHODS: PROWESS inclusion/exclusion criteria were used, except that patients >135 kg were enrolled. Blood samples were collected for steady-state plasma concentration (Css) analysis of activated protein C once each day and for t1/2 analysis after infusion. Weight-normalized clearance (Clp) and t1/2 estimates for DrotAA were calculated and compared between weight groups. RESULTS: Patient weight range was 59–227 kg. There were 32 patients ⩽135 kg and 20 patients >135 kg enrolled. Median Clp was 0.45 L/h/kg (interquartile range [IQR] 0.37–0.54) for patients ⩽135 kg and 0.42 L/h/kg (IQR 0.33–0.54) for patients >135 kg (p = 0.692). Median estimates of Css were 51.9 ng/mL (IQR 43.4–62.0) and 56.5 ng/mL (IQR 44.9–71.1; p = 0.570). In patients ⩽135 kg, DrotAA had a median t1/2 of 16.7 minutes (IQR 13.9–20.0) compared with 16.0 minutes (IQR 12.9–19.8) in patients >135 kg (p = 0.767), for a composite median t1/2 of 16.3 minutes (IQR 14.2–18.8). CONCLUSIONS: There is no statistically significant difference in Css concentrations or t1/2 of DrotAA between patients weighing ⩽135 kg and >135 kg. DrotAA should be dosed by actual body weight.

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Il trattamento di pazienti con sepsi grave mediante drotrecogin alfa: una valutazione economica con riferimento all’Italia

Farmeconomia Health economics and therapeutic pathways ◽

10.7175/fe.v3i3.754 ◽

2002 ◽

Vol 3 (3) ◽

pp. 171-177 ◽

Cited By ~ 3

Author(s):

Carlo Lucioni ◽

Silvio Mazzi ◽

Chinn Christopher

Keyword(s):

Severe Sepsis ◽

Cost Effectiveness ◽

Drotrecogin Alfa ◽

Activated Protein C ◽

Quality Adjusted Life Year ◽

Phase Iii ◽

The Us ◽

Prowess Trial ◽

Standard Values ◽

Clinical Conditions

Sepsis can be defined as a spectrum of clinical conditions caused by the immune response of a host to infection or trauma and characterized by systemic inflammation and coagulation. Particularly in elderly, immunocompromised and critically ill patients, sepsis is a major cause of morbidity and mortality in intensive care units (ICUs) worldwide. In the US, sepsis is the leading cause of death in noncoronary ICU patients. Drotrecogin alfa, or recombinant human activated protein C, has antithrombotic, antiinflammatory, and profibrinolytic properties. Recently in a phase III trial (PROWESS), Drotrecogin alfa demonstrated significantly reduced mortality in severe sepsis patients at 28 days. In this trial important value factors for the assessment of costs and outcomes of severe sepsis were also considered. The purpose of the present study is to determine the economic burden of the treatment with Drotrecogin alfa, according to a cost-effectiveness analysis based on the data of the PROWESS trial. The study has been adapted to the italian health environment. As regards to the costs per surviving patient and costs per QALY (Quality Adjusted Life Year), the predicted cost-effectiveness ratio of drotrecogin alfa in severe sepsis patients is much lower than the standard values considered as acceptable in the international litterature.

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Effect of Human Plasma-Derived Protein C and Murine Recombinant Protein C on Severe Neonatal Sepsis in Mice.

Blood ◽

10.1182/blood.v104.11.689.689 ◽

2004 ◽

Vol 104 (11) ◽

pp. 689-689

Author(s):

Eva-Maria Muchitsch ◽

Hans Peter Schwarz ◽

Katalin Varadi ◽

Charles Esmon ◽

Giuseppe Mancuso ◽

...

Keyword(s):

Severe Sepsis ◽

Mortality Rate ◽

Human Plasma ◽

Neonatal Sepsis ◽

Protein C ◽

Activated Protein C ◽

Risk Of Death ◽

Neonatal Mice ◽

Endogenous Protein ◽

Septic Condition

Abstract Neonatal sepsis is a leading cause of infant morbidity and mortality frequently associated with activation of the coagulation system. Reduced levels of protein C are found in the majority of patients with sepsis and are associated with an increased risk of death. Although activated protein C is indicated for the treatment of severe sepsis in adults, the risk of severe bleeding may limit its use in neonates. Because the likelihood of inducing bleeding with the zymogen form of protein C is reduced we assessed both human and murine protein C zymogen in a murine neonatal sepsis model. In this model neonatal mice were challenged with viable group B streptococci (GBS). The effect of this septic condition on endogenous protein C levels was evaluated and the effect of treatment with either recombinant murine protein C or human plasma-derived (non-activated) protein C (Ceprotin) investigated. During severe GBS sepsis murine endogenous protein C levels decreased over time in neonatal mice, resulting in a maximum decrease of −30 % at 16 hours after GBS challenge and returned towards baseline at 30 hours. Concomitantly, there was an increase in endogenous protein C activation up to 59 % at 6 hours after GBS challenge, returning to baseline levels at 16 hours. Blocking endogenous murine protein C with an anti-mouse monoclonal antibody increased the mortality rate significantly from 62 to 91 %. Treatment of neonatal septic mice (n=36) with 300 U/kg murine protein C subcutaneously 4 hours before GBS challenge decreased the mortality rate significantly in severe sepsis (LD90) to 64 % (p=0.002). Similarly pretreatment with human plasma-derived protein C (200 IU/kg) 4 hours before GBS challenge increased survival rate significantly in severe septic mice. Treatment with 200 IU/kg (Ceprotin) was even effective given 18 hours after GBS challenge, leading to a decrease in the mortality rate in severe sepsis from 87.5 to 48 %. Despite this species difference and the septic condition, human protein C zymogen was activated to activated protein C and detectable in the circulation of mice. This is the first preclinical study were a beneficial effect of a non-activated protein C could be shown in an animal model of severe neonatal sepsis.

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