scholarly journals P072 Evaluation of dosing strategies of anti-TNFα monoclonal antibodies using pharmacokinetic modelling and simulation

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S171-S172
Author(s):  
A Démaris ◽  
A M Grišić ◽  
W Huisinga ◽  
R Walter ◽  
C Kloft
Keyword(s):  
Monoclonal Antibodies ◽  
Body Size ◽  
Fixed Dose ◽  
Dosing Regimen ◽  
Target Concentration ◽  
Concentration Time ◽  
Dosing Strategies ◽  
Dosing Strategy ◽  
The Impact ◽  
Size Descriptor

Abstract Background Anti-TNFα monoclonal antibodies (mAbs) are a well-established treatment for patients with Crohn’s disease (CD). However, subtherapeutic concentrations of mAbs have been related to a loss of response during the first year of therapy1. Therefore, an appropriate dosing strategy is crucial to prevent the underexposure of mAbs for those patients. The aim of our study was to assess the impact of different dosing strategies (fixed dose or body size descriptor adapted) on drug exposure and the target concentration attainment for two different anti-TNFα mAbs: infliximab (IFX, body weight (BW)-based dosing) and certolizumab pegol (CZP, fixed dosing). For this purpose, a comprehensive pharmacokinetic (PK) simulation study was performed. Methods A virtual population of 1000 clinically representative CD patients was generated based on the distribution of CD patient characteristics from an in-house clinical database (n = 116). Seven dosing regimens were investigated: fixed dose and per BW, lean BW (LBW), body surface area, height, body mass index and fat-free mass. The individual body size-adjusted doses were calculated from patient generated body size descriptor values. Then, using published PK models for IFX and CZP in CD patients2,3, for each patient, 1000 concentration–time profiles were simulated to consider the typical profile of a specific patient as well as the range of possible individual profiles due to unexplained PK variability across patients. For each dosing strategy, the variability in maximum and minimum mAb concentrations (Cmax and Cmin, respectively), area under the concentration-time curve (AUC) and the per cent of patients reaching target concentration were assessed during maintenance therapy. Results For IFX and CZP, Cmin showed the highest variability between patients (CV ≈110% and CV ≈80%, respectively) with a similar extent across all dosing strategies. For IFX, the per cent of patients reaching the target (Cmin = 5 µg/ml) was similar across all dosing strategies (~15%). For CZP, the per cent of patients reaching the target average concentration of 17 µg/ml ranged substantially (52–71%), being the highest for LBW-adjusted dosing. Conclusion By using a PK simulation approach, different dosing regimen of IFX and CZP revealed the highest variability for Cmin, the most commonly used PK parameter guiding treatment decisions, independent upon dosing regimen. Our results demonstrate similar target attainment with fixed dosing of IFX compared with currently recommended BW-based dosing. For CZP, the current fixed dosing strategy leads to comparable percentage of patients reaching target as the best performing body size-adjusted dosing (66% vs. 71%, respectively). References

A Systematic Review On Different Prothrombin Complex Concentrate Strategies To Reverse Vitamin K Antagonist Therapy

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3639-3639
Author(s):  
Nakisa Khorsand ◽  
Hilde A.M. Kooistra ◽  
Reinier M. van Hest ◽  
Pharm D ◽  
Nic J.G.M. Veeger ◽  
...  
Keyword(s):  
Systematic Review ◽  
Clinical Outcome ◽  
Quality Assessment ◽  
Vitamin K ◽  
Vitamin K Antagonist ◽  
Factor Ix ◽  
Fixed Dose ◽  
Open Label ◽  
Dosing Strategies ◽  
Dosing Strategy

Abstract Management of patients with a major bleed while on vitamin K antagonist (VKA) is a common clinical challenge. Prothrombin Complex Concentrates (PCC) provide a rapid reversal of VKA induced coagulopathy. The aim of this systematic review is to describe the currently used PCC strategies and to present their efficacy in terms of target INR achievement and clinical outcome. MEDLINE and EMBASE databases were searched for studies reporting the use of PCC for emergency reversal of VKA therapy. Additional inclusion criteria were the reporting of PCC dosing strategy, data on target INR or any clinical outcome or safety parameters, prospective patient enrollment, and a full text publication. All PCC studies in non-VKA patients, case-reports (N<5), duplicates, retrospective studies, and studies on activated PCC were excluded. The quality of selected studies was evaluated using two quality assessment tools which are described by Downs (J Epidemiol Community Health, 1998), and Thomas (McMaster University, 2008). A total of 27 studies was included in which the majority was single cohort (N=18, 67%), open label (N=27, 100%), and/or nonrandomized (N=23, 85%). The total number of included patients was 2410, ranging from 5 to 686 patients per study. One of the included studies was scored as having a strong, 12 a moderate and 14 a weak design. The median quality assessment score was 16 out of 26 [range 10-22]. A large heterogeneity in study parameters was observed including 6 different primary endpoints with 12 different definitions. Fifteen PCC protocols were identified in which the PCC dose ranged from 8 to 50 IU of factor IX/kg or a fixed dose protocol of 200, 500, 1000, or 1500 IU of factor IX/patient. These dosing strategies were based on five principals, namely based on bodyweight (BW), bodyweight and initial INR (BW+INRi), bodyweight and initial INR and target INR (BW+INRi+INRt), individual doctors decision (doctor) or a fixed dose (fixed). The actual infused dosage is depicted in figure 1. Evaluating the used dosing strategy, target INR was reached in 86%, 81%, 78% and 75% of patient in BW, BW+INRi, BW+INRi+INRt and fixed, respectively and was lower (55%) in doctor strategy. Of note, results of the doctor strategy are based on two studies. Clinical outcome was positive for 75%, 93%, 85%, 88% and 67% of patients in strategy BW, BW+INRi, BW+INRi+INRt, fixed, and doctor strategy respectively. Of note, only one study reported on the clinical outcome in the BW+INRi strategy and two in doctor strategy. While our review shows a great diversity on PCC dosing strategies among published data, the same applies to current PCC guidelines in which the ACCP leaves the dosing to the discretion of the physician, the French guidelines recommend a bodyweight adjusted dosing regardless of the INR, the Canadian guidelines recommend three different fixed doses stratified by initial INR, and the Australian guidelines recommend a range of bodyweight adjusted doses from which the physician should decide. Apart from the different dosing strategies, considerable heterogeneity in assessing the impact of PCC treatment was noticed indicating the lack of consensus regarding different aspects of emergency reversal of VKA treatment e.g. optimal target INR, clinical outcome definition. Furthermore, PCC is predominantly studied in small, single-arm and open label settings using the INR to measure its effect rather than clinical outcome. In addition, results from our quality assessment showed that most study designs were at most moderately robust. Evidence gained from the included studies should therefore be interpreted with caution. In conclusion, this review shows that the worst results are reported when a predefined dosing protocol is absent (doctors strategy), while with the use of any treatment protocol good outcome results of PCC treatment are obtained (target INR reached ³ 75%, positive clinical response ³ 75%). A fixed dose strategy seems to be the most simple treatment, with a high potential for optimal clinical outcome while the lowest PCC dosages are infused. Good quality studies with consistent endpoints are needed to guide clinical use. Actual median dose infused in each study(arm). Dots represent the included studies(cohorts) with large, average and small amount of included patients Disclosures: Khorsand: Sanquin BV, Amsterdam: Research Funding.

Economic analysis of alternative pembrolizumab and nivolumab dosing strategies at an academic cancer center.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 6504-6504
Author(s):  
Evan Thomas Hall ◽  
Jenny Zhang ◽  
Eun-Jeong Kim ◽  
Grace Hwang ◽  
Shailender Bhatia ◽  
...  
Keyword(s):  
Cost Minimization ◽  
Pharmaceutical Expenditure ◽  
Cost Savings ◽  
Fixed Dose ◽  
Cancer Center ◽  
Data Repository ◽  
Cancer Therapies ◽  
Medicine Research ◽  
Dosing Strategies ◽  
The Impact

6504 Background: Pembrolizumab (P) and nivolumab (N) were initially investigated and FDA-approved with weight-based dosing strategies, but later the approval label was amended to a fixed dose administration. Given increasing concerns about financial toxicity of cancer therapies, we hypothesize that weight-based dosing of P and N and allowing vial sharing among patients will result in substantial cost savings. Methods: We obtained IRB approval to retrospectively examine all outpatient doses of P and N given at three Stanford Medicine infusion centers between July 1, 2018 and Oct 31, 2018 using the Stanford Medicine Research Data Repository (STARR) database. We performed cost-minimization analysis modeling the impact of dosing strategies based upon patient weight versus fixed dosing (2 mg/kg vs 200 mg q3wks for P; 3 mg/kg vs 240 mg q2wks or 6 mg/kg vs 480 q4wks for N). “Dose-minimization” (DM) was defined as whichever dose was lower (weight-based or fixed dose). The impact of allowing vial sharing (considering commercially available vial sizes) between patients treated at the same site and on the same date was assessed. Average sales price (ASP) from Center for Medicare and Medicaid Services for Part B drugs was used for cost estimates. Results: A total of 1,029 doses of P or N were administered across a variety of cancer types. For most doses (N = 789, 77%), the calculated weight-based dose was less than the fixed dose. DM resulted in decreased usage and expenditures of both P and N, and a further decrease was observed with vial sharing. Total savings estimated with DM and vial sharing strategy were > $1.4 million (Table). This amounted to savings of > 22,000 mg of P (112 fixed doses) and > 11000 mg of N (47 fixed doses). Savings were greatest at the highest volume infusion center. Conclusions: Alternative dosing strategies of P and N would result in significantly less drug utilization and pharmaceutical expenditure without anticipated impact on efficacy. Potential barriers to this approach include existing policies regarding vial sharing and drug vial sizes. [Table: see text]

scholarly journals Population Pharmacokinetic Modeling and Exposure-Response Analysis Providing a Basis for Selecting Penpulimab Dose in a Population with Relapsed/Refractory Classic Hodgkin's Lymphoma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4354-4354
Author(s):  
Benchao Chen ◽  
Xiaopin Jin ◽  
Yongcheng Dong ◽  
Max Wang ◽  
Dennis Xia ◽  
...  
Keyword(s):  
Steady State ◽  
Clinical Studies ◽  
Receptor Occupancy ◽  
Hodgkin's Lymphoma ◽  
Fixed Dose ◽  
Efficacy And Safety ◽  
Dosing Regimen ◽  
Exposure Response ◽  
Concentration Time ◽  
Grade 3

Abstract Background Penpulimab is an IgG1 anti-PD-1 antibody with Fc-engineering to eliminate effector functions. Treatment with penpulimab as a single agent at 1.0, 3.0 and 10.0 mg/kg Q2W cohort were safe during the phase Ia dose-escalation phase with no dose-limiting toxicity observed and 80-100% receptor occupancy being observed in all of the above dose cohorts. It was administered in a fixed dosing regimen [200 mg every 2 weeks (Q2W)] in a phase II study (AK105-201) demonstrating efficacy and safety in Relapsed/Refractory classic Hodgkin's lymphoma (R/R cHL). Longer dosing intervals may offer greater flexibility and convenience to both patients and healthcare professionals. To provide alternative extended dosing schedules for patients receiving penpulimab, we explored the feasibility of a longer dosing regimen [200 mg every 3weeks (Q3W) and 400 mg Q6W] using exposure-response (ER) analysis approach. Methods A penpulimab population PK(PopPK) model was established based on PK data from a total of 332 subjects from six clinical studies. The following PK parameters were determined and used for penpulimab E-R analysis: the trough concentrations at steady-state (C min,ss); the peak concentration at steady-state (C max,ss); area under the concentration-time curve at steady-state (AUC ss). ER evaluation using modeling and simulation was used to demonstrate the similarity of efficacy and safety for 200 mg Q3W and 400 mg Q6W regimens compared with 200 mg Q2W regimen. The efficacy endpoints used in the analysis were complete response (CR), overall response rate (ORR) and disease control rate (DCR) in AK105-201 study and the safety endpoints included ≥ grade 3 treatment-related adverse event (TRAE), ≥ grade 3 immune-related adverse events (irAE), or AE leading to suspension in all the six clinical studies. Result The final PopPK structural model for penpulimab was a two-compartment model with first-order elimination by intravenous infusion. The simulation showed that after multiple doses, the concentration-time curves for 200 mg Q2W or 3 mg/kg Q2w administration were generally consistent. Compared to the 200 mg Q2W regimen, the mean C min,ss of 200 mg Q3W and 400 mg Q6W regimen were approximately 36.5% and 55.5% lower, respectively. However, the fixed-dose simulation (200 mg Q3W, 400 mg Q6W) showed that the C min,ss of 97.5% of the population were higher than 3 μg/mL, 6 times higher than the 90% receptor occupancy concentration in vitro. The C max,ss and AUC ss under the 400 mg Q6W regimen were lower than the observed maximum administered dose (10 mg/kg). Results of the univariate logistic regression analyses evaluating relationships between efficacy (CR, ORR and DCR) and PK exposure (simulated C max,ss, C min,ss, AUC ss) demonstrated a relatively flat ER relationship without dose dependency in R/R cHL patients. The relationship between PK exposure (the same as above) and safety response (≥ grade 3 TRAE, ≥ grade 3 irAE or AE leading to suspension) were also analyzed in patients with different types of cancer, and the result showed no apparent correlation between safety and drug exposure. Conclusions: PopPK simulations and ER analyses indicate that both weight-based dose and fixed-dose (200 mg Q3W or 400 mg Q6W) are appropriate for penpulimab. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Low Etanercept Concentrations in Children With Obesity and Juvenile Idiopathic Arthritis

2021 ◽  
Vol 26 (8) ◽  
pp. 809-814
Author(s):  
Stephen J. Balevic ◽  
Mara L. Becker ◽  
Daniel Gonzalez ◽  
Ryan S. Funk
Keyword(s):  
Juvenile Idiopathic Arthritis ◽  
Body Size ◽  
Drug Exposure ◽  
Plasma Concentrations ◽  
Standard Of Care ◽  
Continuous Measure ◽  
Cross Sectional ◽  
Cdc Guidelines ◽  
Dosing Strategies ◽  
The Impact

OBJECTIVE To evaluate the impact of obesity on etanercept (ETN) drug exposure in children with juvenile idiopathic arthritis (JIA). METHODS We conducted a pilot, cross-sectional, observational study in a real-world cohort of children with JIA receiving ETN as standard of care from a single center. We analyzed the relationship between body size and ETN plasma concentrations, adjusting for dosage. Body size was analyzed as a continuous measure using weight and body mass index (BMI) percentiles and categorically using BMI percentile classifications according to the CDC guidelines. RESULTS We enrolled a total of 29 children. Each child provided one plasma sample for ETN concentration measurement, and all participants were receiving subcutaneous ETN dosed weekly. We observed that the ETN concentration normalized for dose decreased significantly as a function of weight (p = 0.004) and BMI percentile (p = 0.04). Similarly, we observed a progressive decline in mean and median dose-normalized concentrations across higher body size categories. Because of reaching maximum ETN dosage (50 mg), 7 of 8 children (87.5%) with obesity received a weight-based dosage &lt; 0.8 mg/kg/dose. CONCLUSIONS We found that higher body weight and BMI percentile are significantly and negatively associated with ETN drug serum concentration, accounting for differences in dosing. Our data suggest that children who are obese may be routinely under-dosed using current dosing strategies. Inadequate dosing may increase the risk for therapeutic failure and long-term morbidity in a developing child. As a result, characterizing adequate drug exposure in children of all sizes is an important step toward precision dosing.

The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen

Blood ◽  
2005 ◽  
Vol 106 (7) ◽  
pp. 2329-2333 ◽  
Author(s):  
Elizabeth A. Sconce ◽  
Tayyaba I. Khan ◽  
Hilary A. Wynne ◽  
Peter Avery ◽  
Louise Monkhouse ◽  
...  
Keyword(s):  
Body Size ◽  
Warfarin Dose ◽  
Patient Characteristics ◽  
International Normalized Ratio ◽  
Dosing Regimen ◽  
Dose Requirement ◽  
Cyp2c9 Genotype ◽  
Daily Dose ◽  
Warfarin Dosing ◽  
The Impact

AbstractCurrent dosing algorithms do not account for genetic and environmental factors for warfarin dose determinations. This study investigated the contribution of age, CYP2C9 and VKORC1 genotype, and body size to warfarin-dose requirements. Studied were 297 patients with stable anticoagulation with a target international normalized ratio (INR) of 2.0 to 3.0. Genetic analyses for CYP2C9 (*2 and *3 alleles) and VKORC1 (-1639 polymorphism) were performed and venous INR and plasma R- and S-warfarin concentrations determined. The mean warfarin daily dose requirement was highest in CYP2C9 homozygous wild-type patients, compared with those with the variant *2 and *3 alleles (P &lt; .001) and highest in patients with the VKORC1 (position -1639) GG genotype compared with those with the GA genotype and the AA genotype (P &lt; .001). Mean warfarin daily dose requirements fell by 0.5 to 0.7 mg per decade between the ages of 20 to 90 years. Age, height, and CYP2C9 genotype significantly contributed to S-warfarin and total warfarin clearance, whereas only age and body size significantly contributed to R-warfarin clearance. The multivariate regression model including the variables of age, CYP2C9 and VKORC1 genotype, and height produced the best model for estimating warfarin dose (R2 = 55%). Based upon the data, a new warfarin dosing regimen has been developed. The validity of the dosing regimen was confirmed in a second cohort of patients on warfarin therapy.

scholarly journals Pharmacokinetically-guided dosing to improve the efficacy of brigatinib in non-small cell lung cancer patients

2021 ◽  
Author(s):  
Simon Koele ◽  
Stijn van Beek ◽  
Anthonie van der Wekken ◽  
Berber Piet ◽  
Michel van den Heuvel ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Progression Free Survival ◽  
Small Cell ◽  
Small Cell Lung ◽  
Anaplastic Lymphoma ◽  
Dosing Strategies ◽  
Dosing Strategy ◽  
The Impact

Brigatinib was recently approved for the treatment of anaplastic lymphoma kinase-positive non-small cell lung cancer and is dosed according to a one-dose-fits-all paradigm. We aimed to identify a pharmacokinetically-guided precision dosing strategy to improve treatment response with brigatinib through simulations using a previously published pharmacokinetic-pharmacodynamic model. Dosing strategies explored were the approved 180mg QD, the highest tolerable dose tested in clinical trials: 240mg QD, and two precision dosing strategies targeting the median trough concentrations following 180mg QD, and 240mg QD. We investigated the impact of alternative dosing regimens on progression-free survival (PFS), overall survival (OS), and the probability of developing a grade ≥2 rash or grade ≥2 amylase increase. Median PFS and OS increased by 1.6 and 7.8 months, respectively between the currently approved dosing strategy and precision dosing to the median trough concentration of the 240mg dosing strategy, with only a minor increase in the probability of developing toxicity.

scholarly journals Evaluation of Posaconazole Dosing in Children and Young Adults: A Single-Center Review

2021 ◽  
Vol 26 (8) ◽  
pp. 834-840
Author(s):  
Lauren M. Garner ◽  
Susan Ngo ◽  
Jenna Bognaski Kaplan ◽  
William S. Wilson ◽  
Cameron J. McKinzie
Keyword(s):  
Pediatric Patients ◽  
Liver Function Tests ◽  
Current Data ◽  
Dosing Regimen ◽  
Drug Concentrations ◽  
Dosing Regimens ◽  
Dosing Strategies ◽  
Trough Concentrations ◽  
Dosing Strategy ◽  
Dose Modifications

OBJECTIVE Initial posaconazole dosing regimens in children often do not achieve target concentrations, and data continue to support the need for higher initial dosing regimens. The objective of this study is to contribute to the current data regarding suboptimal posaconazole dosing in pediatric patients by retrospectively observing dosing strategies and subsequent drug concentrations. METHODS This study was conducted at a single institution in 27 patients aged 1 to 21 years. Patients who were initiated on any formulation of posaconazole for prophylaxis or treatment while admitted to the hospital were included. The primary outcome was to determine the percentage of pediatric patients who achieved the targeted trough concentration using their initial posaconazole dosing regimen. Secondary outcomes included percentage of patients who experienced a breakthrough invasive fungal infection (IFI), percentage of patients with elevated liver function tests (LFTs), and discontinuation for any reason. RESULTS There were 15 patients (55.5%) who reached desired trough serum concentration after the initial dosing regimen. The number of dose modifications to achieve the desired trough ranged from 1 to 3. Most patients received delayed-release tablets (n = 17), and the average doses for reaching prophylactic and treatment trough concentrations were 6.1 mg/kg/day and 11 mg/kg/day, respectively. There were 2 patients (7.4%) who experienced breakthrough IFI. Overall, 5 patients developed elevated LFTs and 7 patients discontinued treatment early. CONCLUSIONS The results describe a single population of pediatric patients, of whom 55% were able to achieve target trough concentrations of posaconazole with the initial dosing strategy used.

scholarly journals Antimicrobial Therapy in Septic Shock Is Conservative During Resuscitation and Maintenance Phases

2020 ◽  
Vol 36 (4) ◽  
pp. 119-125
Author(s):  
Grace Hsu ◽  
Jeffrey P. Gonzales ◽  
Hyunuk Seung ◽  
Mojdeh S. Heavner ◽  
Wisna Jean ◽  
...  
Keyword(s):  
Septic Shock ◽  
Hospital Length ◽  
Hospital Length Of Stay ◽  
Pharmacokinetic Parameters ◽  
Patient Centered ◽  
Dosing Strategies ◽  
Retrospective Nature ◽  
Medical Intensive Care ◽  
Dosing Strategy ◽  
The Impact

Background: Maximal dosing of early antimicrobials with high loading and maintenance doses may optimize pharmacokinetic parameters to achieve and maintain therapeutic concentrations at the site of infection in septic shock. Little is known about the current practice of early antimicrobial dosing in septic shock. Objective: To characterize early antimicrobial dosing in patients in the resuscitation phase of septic shock. Methods: This retrospective cohort study included patients admitted to the medical intensive care unit (ICU) with septic shock. The primary outcome was the percentage of early antibiotic orders that were maximal or conservative during the resuscitation (0 to 48 hours) phase based on predefined dosing criteria. The secondary outcomes were the correlations of different dosing strategies on hospital length of stay (LOS), ICU LOS, and hospital mortality. Results: This study evaluated 161 patients and 692 antibiotic orders; 504 (72.8%) of the orders during the resuscitation phase were conservative. There were no differences in mortality (odds ratio = 0.66; 95% confidence interval = 0.35-1.25; P = .20), hospital LOS (median = 20 [interquartile range (IQR) = 10-34] vs 19 [IQR = 11-32] days; P = .93), or ICU LOS (median = 8 [IQR = 5-16] vs 9 [IQR = 5-15] days; P = .63) between maximal and conservative dosing groups, respectively, in the resuscitation phase. Limitations of this study included the use of institution-specific antimicrobial dosing guidelines and its retrospective nature. Conclusions: Early antibiotic dosing is conservative for a majority of patients in septic shock. Future studies are needed to evaluate the impact of dosing strategy on patient-centered outcomes in septic shock.

scholarly journals The Impact on Infectivity and Neutralization Efficiency of SARS-CoV-2 Lineage B.1.351 Pseudovirus

Viruses ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 633
Author(s):  
Yeong Jun Kim ◽  
Ui Soon Jang ◽  
Sandrine M. Soh ◽  
Joo-Youn Lee ◽  
Hye-Ra Lee
Keyword(s):  
South Africa ◽  
Monoclonal Antibodies ◽  
Cell Fusion ◽  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
Receptor Binding Domain ◽  
Viral Spread ◽  
New Variant ◽  
Global Concern ◽  
The Impact

A new variant of SARS-CoV-2 B.1.351 lineage (first found in South Africa) has been raising global concern due to its harboring of multiple mutations in the spike that potentially increase transmissibility and yield resistance to neutralizing antibodies. We here tested infectivity and neutralization efficiency of SARS-CoV-2 spike pseudoviruses bearing particular mutations of the receptor-binding domain (RBD) derived either from the Wuhan strains (referred to as D614G or with other sites) or the B.1.351 lineage (referred to as N501Y, K417N, and E484K). The three different pseudoviruses B.1.351 lineage related significantly increased infectivity compared with other mutants that indicated Wuhan strains. Interestingly, K417N and E484K mutations dramatically enhanced cell–cell fusion than N501Y even though their infectivity were similar, suggesting that K417N and E484K mutations harboring SARS-CoV-2 variant might be more transmissible than N501Y mutation containing SARS-CoV-2 variant. We also investigated the efficacy of two different monoclonal antibodies, Casirivimab and Imdevimab that neutralized SARS-CoV-2, against several kinds of pseudoviruses which indicated Wuhan or B.1.351 lineage. Remarkably, Imdevimab effectively neutralized B.1.351 lineage pseudoviruses containing N501Y, K417N, and E484K mutations, while Casirivimab partially affected them. Overall, our results underscore the importance of B.1.351 lineage SARS-CoV-2 in the viral spread and its implication for antibody efficacy.

Albumin Utilization in Spontaneous Bacterial Peritonitis

2021 ◽  
pp. 089719002199700
Author(s):  
Alex M. Ebied ◽  
Thakul Rattanasuwan ◽  
Yiqing Chen ◽  
Adonice P. Khoury
Keyword(s):  
High Risk ◽  
Spontaneous Bacterial Peritonitis ◽  
Total Bilirubin ◽  
Kidney Injury ◽  
Inclusion Criteria ◽  
Dosing Regimen ◽  
Bacterial Peritonitis ◽  
Risk Patients ◽  
The Impact ◽  
Order Set

Background: Albumin has been shown to decrease the incidence of mortality and acute kidney injury (AKI) in patients with spontaneous bacterial peritonitis (SBP). Albumin administration in SBP is recommended within 6 hours of diagnosis and for reserved use in high-risk patients with the following baseline laboratory tests: serum creatinine >1 mg/dL, blood urea nitrogen >30 mg/dL or total bilirubin >4 mg/dL. Objective: We aimed to assess the impact of an albumin order set restricted to high-risk SBP. Methods: A retrospective cohort study was conducted between Jan 1, 2013 to Feb 28, 2018. The albumin order set was implemented on Sep 20, 2016. Patients were included if they were diagnosed with SBP and had an ascitic fluid polymorphonuclear count ≥ 250 cells/mm3. Results: Out of a total of 137 patients reviewed, 88 met the inclusion criteria. The incidence of AKI in the pre-order set and post-order set were 63.93% and 33.33% (p = 0.01), respectively. The incidence of mortality in the pre-order set and post-order set were 36.07% and 7.41% (p = 0.005), respectively. The percentage of patients administered albumin within 6 hours were 24.59% to 40.74% (p = 0.14) in the pre-order set and post-order set, respectively. The percentage of patients who received the recommended albumin dosing regimen ordered was 42.62% vs 96.30% (p < 0.001), in the pre-order set and post-order set, respectively. Conclusion: The albumin order set restricted to high-risk SBP patients significantly reduced the incidence of AKI and mortality, and improved the appropriateness of albumin regimen ordered.

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