Objective: We aimed to characterize the pharmacokinetics and pharmacodynamics of drotrecogin alfa (activated) (recombinant human activated protein C) in patients with severe sepsis.
Methods: Patients (N = 1690) in a randomized, double-blind, placebo-controlled phase 3 trial received a 96-hour infusion of placebo (n = 840) or drotrecogin alfa (activated) (n = 850), 24 microg x kg(-1) x h(-1). Plasma samples from 680 patients were collected for pharmacokinetic assessment. Pharmacodynamic effects on activated partial thromboplastin time, D-dimer, protein C, and interleukin 6 were analyzed by drotrecogin alfa (activated) steady-state plasma concentration (C(ss)) quartile.
Results: Transient endogenous activated protein C concentrations above 10 ng/mL were observed in 11 placebo-treated patients (3.3%). In drotrecogin alfa (activated)-treated patients, the median C(ss) was 44.9 ng/mL and the median plasma clearance (CL(p)) was 40.1 L/h. C(ss) was reached within 2 hours after the infusion was started. Plasma concentrations were below the assay quantitation limit of 10 ng/mL within 2 hours after the infusion was stopped in 92% of patients. CL(p) increased with increasing body weight, so infusion rates should be based on predose body weight. Mean CL(p) associated with age, sex, or baseline hepatic or renal function differed by less than 30% from the mean CL(p) in all patients and resided within the interquartile range of CL(p) in all patients. Dose adjustment is not required on the basis of these factors alone or in combination. No correlation was detected between C(ss) quartile and bleeding risk or the magnitudes of effect on biomarkers of coagulopathy (D-dimers and protein C) and inflammation (interleukin 6).
Conclusions: Plasma concentrations of drotrecogin alfa (activated) attain steady state rapidly after the infusion is started and decline rapidly after the infusion is stopped. The infusion rate should be based on predose body weight and not on any other demographic or baseline clinical covariate.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1067/mcp.2002.128148 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Hydrocortisone plus fludrocortisone for community acquired pneumonia-related septic shock: a subgroup analysis of the APROCCHSS phase 3 randomised trial.
Lancet Respir Med
May 2024
Department of Intensive Care, Raymond Poincaré Hospital, APHP University Versailles Saint Quentin-University Paris Saclay, Garches, France; Institut Hospitalo Universitaire PROMETHEUS, Garches, France; Laboratory of Infection & Inflammation-U1173, School of Medicine, INSERM, University Versailles Saint Quentin-University Paris Saclay, Garches, France; FHU SEPSIS, Garches, France. Electronic address:
Article Synopsis
- The study explores the effectiveness of hydrocortisone and fludrocortisone treatments in patients with septic shock caused by community-acquired pneumonia (CAP) compared to non-CAP cases.
- It includes data from the phase 3 APROCCHSS trial, which initially tested these treatments across multiple centers in France, focusing specifically on how they impact mortality outcomes.
- Results indicate that patients with CAP may respond differently to these treatments, and various mortality rates and recovery metrics were analyzed to determine the overall benefit of the steroid regimen.
Recombinant Activated Protein C (rhAPC) Affects Lipopolysaccharide-Induced Mechanical Compliance Changes and Beat Frequency of mESC-Derived Cardiomyocyte Monolayers.
Shock
April 2022
Institute for Bioengineering, University of Applied Sciences Aachen/Campus Juelich, Juelich, Germany.
Background: Septic cardiomyopathy increases mortality by 70% to 90% and results in mechanical dysfunction of cells.
Methods: Here, we created a LPS-induced in-vitro sepsis model with mouse embryonic stem cell-derived cardiomyocytes (mESC-CM) using the CellDrum technology which simultaneously measures mechanical compliance and beat frequency of mESCs. Visualization of reactive oxygen species (ROS), actin stress fibers, and mRNA quantification of endothelial protein C receptor (EPCR) and protease-activated receptor 1 (PAR1) before/after LPS incubation were used for method validation.
Old drug, new Trick? The rationale for the treatment of COVID-19 with activated protein C.
Med Hypotheses
April 2021
Tufts University School of Medicine, Department of Medicine, Newton-Wellesley Hospital, 2014 Washington Street, Newton, MA 02462, USA. Electronic address:
As the COVID-19 pandemic continues, researchers seek to identify efficacious treatments. Current approaches to COVID-19 therapeutics focus on antiviral agents, convalescent plasma, monoclonal antibodies, immunomodulators and more traditional therapies such as steroids [1-6]. Reversing disturbances in coagulation has also been identified as a priority area for candidate therapies, such as through the Accelerating COVID-19 Therapeutic Interventions and Vaccines 4 adaptive clinical trial (ACTIV-4) which is currently evaluating aspirin, heparins and apixaban [7].
View Article and Find Full Text PDFHealth economic evaluations of sepsis interventions in critically ill adult patients: a systematic review.
J Intensive Care
January 2020
3Centre for Health Economics, Monash University, Melbourne, Victoria Australia.
Background: Sepsis is a global health priority. Interventions to reduce the burden of sepsis need to be both effective and cost-effective. We performed a systematic review of the literature on health economic evaluations of sepsis treatments in critically ill adult patients and summarised the evidence for cost-effectiveness.
View Article and Find Full Text PDFIs tri-iodothyronine a better choice than activated protein C in sepsis treatment?
Ulus Travma Acil Cerrahi Derg
November 2019
Department of General Surgery, Sancaktepe Training and Research Hospital, İstanbul-Turkey.
Background: Sepsis can be defined as a life-threatening organ dysfunction due to a dysregulated host response to infection. In sepsis, the coagulation cascade is activated and the balance shifts to the procoagulant side. Recently, the use of protein C is proposed for the treatment of sepsis.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!