scholarly journals Development of a long-acting direct-acting antiviral system for hepatitis C virus treatment in swine

2020 ◽  
Vol 117 (22) ◽  
pp. 11987-11994
Author(s):  
Malvika Verma ◽  
Jacqueline N. Chu ◽  
John A. F. Salama ◽  
Mohammed T. Faiz ◽  
Feyisope Eweje ◽  
...  
Keyword(s):  
Cost Effectiveness ◽  
Hepatitis C ◽  
High Risk ◽  
Release Kinetics ◽  
Cost Effective ◽  
Direct Acting Antiviral ◽  
Long Acting ◽  
Direct Acting

Chronic hepatitis C virus (HCV) infection is a leading cause of cirrhosis worldwide and kills more Americans than 59 other infections, including HIV and tuberculosis, combined. While direct-acting antiviral (DAA) treatments are effective, limited uptake of therapy, particularly in high-risk groups, remains a substantial barrier to eliminating HCV. We developed a long-acting DAA system (LA-DAAS) capable of prolonged dosing and explored its cost-effectiveness. We designed a retrievable coil-shaped LA-DAAS compatible with nasogastric tube administration and the capacity to encapsulate and release gram levels of drugs while resident in the stomach. We formulated DAAs in drug–polymer pills and studied the release kinetics for 1 mo in vitro and in vivo in a swine model. The LA-DAAS was equipped with ethanol and temperature sensors linked via Bluetooth to a phone application to provide patient engagement. We then performed a cost-effectiveness analysis comparing LA-DAAS to DAA alone in various patient groups, including people who inject drugs. Tunable release kinetics of DAAs was enabled for 1 mo with drug–polymer pills in vitro, and the LA-DAAS safely and successfully provided at least month-long release of sofosbuvir in vivo. Temperature and alcohol sensors could interface with external sources for at least 1 mo. The LA-DAAS was cost-effective compared to DAA therapy alone in all groups considered (base case incremental cost-effectiveness ratio $39,800). We believe that the LA-DAA system can provide a cost-effective and patient-centric method for HCV treatment, including in high-risk populations who are currently undertreated.

Cost-effectiveness and budget impact of interferon-free direct-acting antiviral-based regimens for hepatitis C treatment: the French case

2016 ◽  
Vol 23 (10) ◽  
pp. 767-779 ◽  
Author(s):  
S. Deuffic-Burban ◽  
D. Obach ◽  
V. Canva ◽  
S. Pol ◽  
F. Roudot-Thoraval ◽  
...  
Keyword(s):  
Cost Effectiveness ◽  
Hepatitis C ◽  
Budget Impact ◽  
Hepatitis C Treatment ◽  
Direct Acting Antiviral ◽  
French Case ◽  
Direct Acting

Engagement in Care of High-Risk Hepatitis C Patients with Interferon-Free Direct-Acting Antiviral Therapies

2017 ◽  
Vol 62 (6) ◽  
pp. 1472-1479 ◽  
Author(s):  
John B. Dever ◽  
Julie H. Ducom ◽  
Ariel Ma ◽  
Joseph Nguyen ◽  
Lin Liu ◽  
...  
Keyword(s):  
Hepatitis C ◽  
High Risk ◽  
Engagement In Care ◽  
Direct Acting Antiviral ◽  
Antiviral Therapies ◽  
Direct Acting

scholarly journals Design and Characterization of Combinational Domperidone-Famotidine Floating Drug Delivery System - In vitro and In vivo studies

2021 ◽  
Vol 62 (2) ◽  
pp. 144-162
Author(s):  
Mounika Chidurala ◽  
Raveendra Reddy J
Keyword(s):  
Drug Release ◽  
Oral Administration ◽  
Quality By Design ◽  
Release Kinetics ◽  
Cost Effective ◽  
Fickian Diffusion ◽  
In Vivo Studies ◽  
Pharmacokinetic Studies

Introduction: The drawbacks assosiated with oral administration of drugscan be controlled or minimized by gastro retentive formulations that remain buoyant within the stomach for an extended time by providing prolonged gastric retention and releasethe drug in an exceedingly extended manner thereby improving bioavailability. The current research was to develop and optimize Domperidone and Famotidine floating tablets with extended release by Quality by Design approach. Method: Based on QTPP (Quality Target Product Profile), CQAs (Critical Quality Attributes)wereidentified. Risk analysis by the evaluation of formulation and process parameters showed that optimizing the levels of polymers could reduce high risk to achieve the target profile. A 23factor experimental design with midpoints was selected for statistical analysis and optimization. Results: HPMC K100 and Carbopol 934P had a positive effect while ethyl cellulose demonstrated a negative effect on the selected responses. Drug release kinetics followed the first-order release with Higuchi diffusion and Fickian diffusion. Optimized formula satisfying all the required parameters was selected and evaluated. The predicted response values were in close agreement with experimental response values. Abdominal X-ray imaging after oral administration of the tablets on a healthy rabbit’s stomach confirmed the extended floating behavior with shorter lag time. In vivo, pharmacokinetic studies in rabbits revealed that the optimized formulation exhibited prolonged drug release with enhanced Cmax, tmax, AUCo-t, and t1/2 of an optimized product when compared to the marketed product. Conclusions: It has been concluded that the application of Quality by Design in the formulation and optimization reduced the number of trials to produce a cost-effective formula.

Quality by Design enabled anti-hypertensive Floating drug delivery system by Risk assessment and Design of Experiment (DoE) – In vitro – In vivo correlation studies

2021 ◽  
Vol 16 ◽  
Author(s):  
Mounika Chidurala ◽  
Raveendra Reddy J
Keyword(s):  
Drug Release ◽  
Risk Analysis ◽  
Quality By Design ◽  
Release Kinetics ◽  
Cost Effective ◽  
Fickian Diffusion ◽  
In Vivo Studies ◽  
Pharmacokinetic Studies

Background: The present research aimed to develop and optimize extended-release floating tablets of Sacubitril and Valsartan through Quality by Design (QbD) approach. Risk analysis by formulation assessment and process parameters showed that optimizing the levels of the polymer will minimize high risk to meet the target profile. A two (2) level three (3) full factorial experimental design along with midpoints was carefully chosen for optimization and statistical analysis. Based on the literature, the independent and dependent variables were selected. Results: HPMC K100, Carbopol 934P had a positive effect, whereas Ethylcellulose had a negative effect on Floating time, drug release at 2 h, drug release at 12 h and, 50% responses. Drug release kinetics followed the first-order release with Higuchi and Fickian diffusion. Contour and overlay plots were utilized for an assortment of design space and optimized formula. ANOVA results of all the factors exhibited significance at p<0.05. Abdominal X-ray imaging of the optimized tablets on healthy rabbit’s stomach confirmed the floating behavior for more than 12 h. In vivo pharmacokinetic studies in rabbits showed that the optimized formulation exhibited prolonged and extended drug release with improved Cmax, tmax, AUCo-t, and t1/2 of test product when compared to marketed product. IVIVC model was developed by using dissolution data of in vitro and pharmacokinetics data of in-vivo by de-convolution method (Wagner-Nelson method). Conclusion: The Quality by Design implementation in the formulation and optimization abridged the number of trials to produce a cost-effective formula. In vivo studies confirmed that the formula was successfully developed with extended floating time (12 h) and drug release by risk analysis and experimental designs. Level A correlation was observed which confirmed a good correlation between in vitro and in vivo data.

scholarly journals Cost-Effectiveness Analysis of Direct-Acting Antiviral Agents for Occupational Hepatitis C Infections in Germany

2020 ◽  
Vol 17 (2) ◽  
pp. 440
Author(s):  
Melanie Runge ◽  
Magdalene Krensel ◽  
Claudia Westermann ◽  
Dominik Bindl ◽  
Klaus Nagels ◽  
...  
Keyword(s):  
Cost Effectiveness ◽  
Hepatitis C ◽  
Antiviral Agents ◽  
Base Case ◽  
German Statutory Accident Insurance ◽  
Direct Acting Antiviral ◽  
Life Years ◽  
Direct Acting ◽  
Direct Acting Antiviral Agents

Around 1% of the world’s population is infected with hepatitis C. The introduction of new direct-acting antiviral agents (DAAs) in 2014 has substantially improved hepatitis C treatment outcomes. Our objective was to evaluate the long-term cost effectiveness of DAAs in health care personnel (HP) with confirmed occupational diseases in Germany. A standardised database from a German statutory accident insurance was used to analyse the cost-effectiveness ratio for the DAA regimen in comparison with interferon-based triple therapies. Taking account of the clinical progression of the disease, a Markov model was applied to perform a base case analysis for a period of 20 years. The robustness of the results was determined using a univariate deterministic sensitivity analysis. The results show that treatment with DAAs is more expensive, but also more effective than triple therapies. The model also revealed that the loss of 3.23 life years can be averted per patient over the 20 years. Compared to triple therapies, DAA treatment leads to a higher sustained virologic response (SVR). Although this results in a decrease of costs in the long term, e.g., pension payments, DAA therapy will cause greater expense in the future due to the high costs of the drugs.

Inhibitory Effects of Amentoflavone and Orobol on Daclatasvir-Induced Resistance-Associated Variants of Hepatitis C Virus

2018 ◽  
Vol 46 (04) ◽  
pp. 835-852 ◽  
Author(s):  
Wei-Ping Lee ◽  
Keng-Li Lan ◽  
Shi-Xian Liao ◽  
Yi-Hsiang Huang ◽  
Ming-Chih Hou ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Viral Entry ◽  
Antiviral Agents ◽  
Cost Effective ◽  
Pegylated Interferon ◽  
Chinese Herbs ◽  
Inhibitory Effects ◽  
Direct Acting Antiviral ◽  
Direct Acting

Hepatitis C virus (HCV) is recognized as a major causative agent of chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Despite rapid progress in the development of direct-acting antivirals (DAA) against HCV infection in recent years, cost-effective antiviral drugs with more affordable prices still need to be developed. In this study, we screened a library of natural compounds to identify natural HCV inhibitors. The library of the pure compounds extracted from Chinese herbs deposited in the chemical bank of National Research Institute of Chinese Medicine (NRICM), Taiwan was screened in the cell culture-derived HCV (HCVcc) system. We identified the flavone or flavan-based compounds amentoflavone, 7,4[Formula: see text]-dihydroxyflavanone, and orobol with the inhibition of viral entry, replication, and translation of the HCV life cycle. Amentoflavone and orobol also showed inhibitory effects on resistant-associated variants to the NS5A inhibitor daclatasvir. The results of this study have the potential to benefit patients who are intolerant to the adverse effect of pegylated interferon or who harbor resistant strains refractory to treatment by current direct-acting antiviral agents.

scholarly journals Preclinical Profile and Clinical Efficacy of a Novel Hepatitis C Virus NS5A Inhibitor, EDP-239

2016 ◽  
Vol 60 (10) ◽  
pp. 6207-6215 ◽  
Author(s):  
Christopher M. Owens ◽  
Bradley B. Brasher ◽  
Alex Polemeropoulos ◽  
Michael H. J. Rhodin ◽  
Nicole McAllister ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Nonstructural Protein ◽  
Viral Rna ◽  
Controlled Clinical Trial ◽  
Genotype 1A ◽  
Pharmacokinetic Properties ◽  
Direct Acting

ABSTRACTEDP-239, a novel hepatitis C virus (HCV) inhibitor targeting nonstructural protein 5A (NS5A), has been investigatedin vitroandin vivo. EDP-239 is a potent, selective inhibitor with potency at picomolar to nanomolar concentrations against HCV genotypes 1 through 6. In the presence of human serum, the potency of EDP-239 was reduced by less than 4-fold. EDP-239 is additive to synergistic with other direct-acting antivirals (DAAs) or host-targeted antivirals (HTAs) in blocking HCV replication and suppresses the selection of resistancein vitro. Furthermore, EDP-239 retains potency against known DAA- or HTA-resistant variants, with half-maximal effective concentrations (EC50s) equivalent to those for the wild type. In a phase I, single-ascending-dose, placebo-controlled clinical trial, EDP-239 demonstrated excellent pharmacokinetic properties that supported once daily dosing. A single 100-mg dose of EDP-239 resulted in reductions in HCV genotype 1a viral RNA of >3 log10IU/ml within the first 48 h after dosing and reductions in genotype 1b viral RNA of >4-log10IU/ml within 96 h. (This study has been registered at ClinicalTrials.gov under identifier NCT01856426.)

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