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

2005 ◽  
Vol 39 (2) ◽  
pp. 262-267 ◽  
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.

Unfractionated heparin infusion for treatment of venous thromboembolism based on actual body weight without dose capping

2019 ◽  
Vol 25 (1) ◽  
pp. 47-54 ◽  
Author(s):  
Julia A Shlensky ◽  
Kristina M Thurber ◽  
John G O’Meara ◽  
Narith N Ou ◽  
Jennifer L Osborn ◽  
...  
Keyword(s):  
Body Weight ◽  
Venous Thromboembolism ◽  
Actual Body ◽  
Unfractionated Heparin ◽  
Obese Group ◽  
Morbidly Obese ◽  
Actual Body Weight ◽  
Bleeding Events ◽  
Heparin Infusion ◽  
Significant Difference

Controversy exists regarding the use of dose capping of weight-based unfractionated heparin (UFH) infusions in obese and morbidly obese patients. The primary objective of this study was to compare time to first therapeutic activated partial thromboplastin time (aPTT) in hospitalized patients receiving UFH for acute venous thromboembolism (VTE) among three body mass index (BMI) cohorts: non-obese (< 30 kg/m2), obese (30–39.9 kg/m2), and morbidly obese (⩾ 40 kg/m2). In this single-center, retrospective cohort study, patients were included if they ⩾ 18 years of age, had a documented VTE, and were on an infusion of UFH for at least 24 hours. Weight-based UFH doses were calculated using actual body weight. A total of 423 patients met the inclusion criteria, with 230 (54.4%), 146 (34.5%), and 47 (11.1%) patients in the non-obese, obese, and morbidly obese cohorts, respectively. Median times to therapeutic aPTT were 16.4, 16.6, and 17.1 hours in each cohort. Within 24 hours, the cumulative incidence rates for therapeutic aPTT were 70.7% for the non-obese group, 69.9% for the obese group, and 61.7% for the morbidly obese group (obese vs non-obese: HR = 1.02, 95% CI: 0.82–1.26, p = 0.88; morbidly obese vs non-obese: HR = 0.87, 95% CI: 0.62–1.21, p = 0.41). There was no significant difference in major bleeding events between BMI groups (obese vs non-obese, p = 0.91; morbidly obese vs non-obese, p = 0.98). Based on our study, heparin dosing based on actual body weight without a dose cap is safe and effective.

Bleeding Complications with Drotrecogin Alfa Activated (Xigris®): A Retrospective Review of 31 Operative and 68 Non-Operative Patients with Severe Sepsis

2008 ◽  
Vol 74 (10) ◽  
pp. 898-901
Author(s):  
Benedict J.W. Taylor ◽  
Sarah J. Lee ◽  
Kenneth Waxman
Keyword(s):  
Severe Sepsis ◽  
Intracranial Hemorrhage ◽  
Drotrecogin Alfa ◽  
Surgical Patients ◽  
Bleeding Complications ◽  
Serious Adverse Event ◽  
Risk Of Bleeding ◽  
Drotrecogin Alfa Activated ◽  
Significant Difference ◽  
Nonsurgical Patients

We reviewed 100 consecutive patients who received Drotrecogin alfa (activated) (DAA) (Xigris®, Eli Lilly, Indianapolis, IN) for the treatment of severe sepsis and compared the incidence of bleeding complications in surgical (n = 30) and nonsurgical cohorts (n = 70). Thirty patients who received DAA therapy for severe sepsis underwent one or more contemporaneous surgical procedures. These were compared with 70 DAA patients who did not undergo surgery. During the course of DAA administration, transfusion of greater than three units of blood, an intracranial hemorrhage, or other bleeding serious adverse event were qualified as bleeding complications. Overall, we identified seven patients who fulfilled the designated bleeding complication criteria, four in the surgical cohort, and three in the nonsurgical cohort. There was no significant difference in the rate of bleeding complications between surgical and nonsurgical cohorts (P = 0.1063). Moreover, there were no mortalities ascribed to bleeding and there were no intracranial hemorrhage events. All bleeding complications were due to a drop in hemoglobin or platelets only, and were treated with transfusion. Our experience demonstrates that there is an equivalent risk of bleeding for surgical patients treated with DAA compared with nonsurgical patients. Additionally, all bleeding complications were amenable to simple transfusion.

scholarly journals Dosing and Pharmacokinetics of Polymyxin B in Patients with Renal Insufficiency

2016 ◽  
Vol 61 (1) ◽  
Author(s):  
Visanu Thamlikitkul ◽  
Yanina Dubrovskaya ◽  
Pooja Manchandani ◽  
Thundon Ngamprasertchai ◽  
Adhiratha Boonyasiri ◽  
...  
Keyword(s):  
Renal Function ◽  
Body Weight ◽  
Steady State ◽  
Renal Insufficiency ◽  
Actual Body ◽  
Normal Renal Function ◽  
Polymyxin B ◽  
Poor Correlation ◽  
Actual Body Weight ◽  
Significant Difference

ABSTRACT Polymyxin B remains the last-line treatment option for multidrug-resistant Gram-negative bacterial infections. Current U.S. Food and Drug Administration-approved prescribing information recommends that polymyxin B dosing should be adjusted according to the patient's renal function, despite studies that have shown poor correlation between creatinine and polymyxin B clearance. The objective of the present study was to determine whether steady-state polymyxin B exposures in patients with normal renal function were different from those in patients with renal insufficiency. Nineteen adult patients who received intravenous polymyxin B (1.5 to 2.5 mg/kg [actual body weight] daily) were included. To measure polymyxin B concentrations, serial blood samples were obtained from each patient after receiving polymyxin B for at least 48 h. The primary outcome was polymyxin B exposure at steady state, as reflected by the area under the concentration-time curve (AUC) over 24 h. Five patients had normal renal function (estimated creatinine clearance [CLCR] ≥ 80 ml/min) at baseline, whereas 14 had renal insufficiency (CLCR < 80 ml/min). The mean AUC of polymyxin B ± the standard deviation in the normal renal function cohort was 63.5 ± 16.6 mg·h/liter compared to 56.0 ± 17.5 mg·h/liter in the renal insufficiency cohort (P = 0.42). Adjusting the AUC for the daily dose (in mg/kg of actual body weight) did not result in a significant difference (28.6 ± 7.0 mg·h/liter versus 29.7 ± 11.2 mg·h/liter, P = 0.80). Polymyxin B exposures in patients with normal and impaired renal function after receiving standard dosing of polymyxin B were comparable. Polymyxin B dosing adjustment in patients with renal insufficiency should be reexamined.

New and Emerging Therapies for Sepsis

2002 ◽  
Vol 36 (4) ◽  
pp. 648-654 ◽  
Author(s):  
Daniel P Healy
Keyword(s):  
Severe Sepsis ◽  
Inflammatory Response ◽  
Protein C ◽  
Drotrecogin Alfa ◽  
Activated Protein C ◽  
Antibody Fragment ◽  
Phase Iii ◽  
Human Form ◽  
Risk Of Death ◽  
Phase Iii Trials

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.

Drotrecogin alfa (activated) treatment in severe sepsis from the global open-label trial ENHANCE: Further evidence for survival and safety and implications for early treatment*

2005 ◽  
Vol 33 (10) ◽  
pp. 2266-2277 ◽  
Author(s):  
Jean-Louis Vincent ◽  
Gordon R. Bernard ◽  
Richard Beale ◽  
Christopher Doig ◽  
Christian Putensen ◽  
...  
Keyword(s):  
Severe Sepsis ◽  
Early Treatment ◽  
Drotrecogin Alfa ◽  
Open Label ◽  
Drotrecogin Alfa Activated ◽  
Open Label Trial

Toxicity and effectiveness of carboplatin in obese or overweight patients

2018 ◽  
Vol 25 (6) ◽  
pp. 1328-1335 ◽  
Author(s):  
Cristina Grueso Cuesta ◽  
Jaime E Poquet Jornet ◽  
Juan M Gasent Blesa ◽  
Antonio Valdivia Perez ◽  
Francisco J Carrera Hueso ◽  
...  
Keyword(s):  
Overall Survival ◽  
Body Weight ◽  
Actual Body ◽  
Response Rate ◽  
Progression Free Survival ◽  
Normal Weight ◽  
Actual Body Weight ◽  
Free Survival ◽  
Significant Difference ◽  
Dose Reductions

Objective To evaluate the efficiency and toxicity of carboplatin using actual body weight in obese/overweight patients using the Calvert formula with Cockcroft–Gault for CrCl estimation. Methods We evaluated the association of BMI in regards to efficiency and toxicity in a retrospective cohort study of patients who started treatment with carboplatin between 2012 and 2013. Cohorts included obese/overweight patients and normal-weight patients. Efficiency was measured by overall survival, progression-free survival and response rate. Toxicity was measured by the proportion of dose reductions and delays of chemotherapy cycles. We utilized a bivariate and multivariate analysis. Results Eighty-six patients were included in the study (50% obese/overweight). There was not a statistically significant difference in effectiveness and toxicity between the two groups in BMI. In the multivariate analysis, BMI not was associated with overall survival (hazard ratio: 0.95, 95% CI: 0.54–1.66, p = 0.849), progression-free survival (hazard ratio: 0.91; 95% CI: 0.54–1.54; p = 0.732), cycle delays (odds ratio (OR): 1.47, 95% CI: 0.80–2.69, p = 0.218) or carboplatin dose reductions (OR: 0.87, 95% CI: 0.35–2.15, p = 0.760). Response rate was 53.5% in both groups. Conclusions In our study, obese and overweight cancer patients did not show a statistically significant difference in terms of effectiveness and toxicity compared to normal-weight cancer patients who were treated with carboplatin using their actual body weight with the Calvert formula and Cockcroft–Gault for CrCl estimation. Therefore, it was appropriate to use the actual body weight for our patients.

scholarly journals Daptomycin Dosing Based on Ideal Body Weight versus Actual Body Weight: Comparison of Clinical Outcomes

2013 ◽  
Vol 58 (1) ◽  
pp. 88-93 ◽  
Author(s):  
Jennifer K. Ng ◽  
Lucas T Schulz ◽  
Warren E. Rose ◽  
Barry C. Fox ◽  
David R. Andes ◽  
...  
Keyword(s):  
Body Weight ◽  
Actual Body ◽  
Clinical Success ◽  
Infection Type ◽  
Ideal Body Weight ◽  
Actual Body Weight ◽  
Success Rates ◽  
Content Type ◽  
Significant Difference ◽  
Ideal Body

ABSTRACTDaptomycin use at our institution changed to ideal body weight dosing based on a published analysis of pharmacokinetic-pharmacodynamic efficacy target attainment, bacterial ecology, and a desire to reduce drug toxicity. The current study compared outcomes between actual body weight and ideal body weight dosing of daptomycin before and after this intervention. In the evaluable group, 69 patients received doses based on actual body weight and 48 patients received doses based on ideal body weight. Patients were treated for documentedEnterococcusspecies,Staphylococcus aureus, or coagulase-negativeStaphylococcusinfections, including bloodstream, intraabdominal, skin and soft tissue, urinary, and bone. There was no statistically significant difference in clinical success between the groups (88.9% for actual body weight compared to 89.1% for ideal body weight,P= 0.97). After we adjusted for gender, age, body mass index, concomitant 3-hydroxy-3-methylglutaryl–coenzyme A reductase inhibitors, infection type, and organism type, clinical success rates remained similar between groups (adjusted odds ratio of 0.68 in favor of actual body weight, 95% confidence interval [CI] of 0.13 to 3.55). Microbiological outcomes, length of stay, mortality, and adverse effects were also similar between groups. Further studies are warranted to confirm that ideal body weight dosing provides similar outcomes to actual body weight dosing for all patients and types of infections and organisms.

ENHANCE: Results of a global open-label trial of drotrecogin alfa (activated) in children with severe sepsis*

2006 ◽  
Vol 7 (3) ◽  
pp. 200-211 ◽  
Author(s):  
Brahm Goldstein ◽  
Simon Nadel ◽  
Mark Peters ◽  
Roger Barton ◽  
Flavia Machado ◽  
...  
Keyword(s):  
Severe Sepsis ◽  
Drotrecogin Alfa ◽  
Open Label ◽  
Drotrecogin Alfa Activated ◽  
Open Label Trial
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