scholarly journals Pharmacokinetics, Pharmacodynamics, and Tolerability of GS-9851, a Nucleotide Analog Polymerase Inhibitor, following Multiple Ascending Doses in Patients with Chronic Hepatitis C Infection

2012 ◽  
Vol 57 (3) ◽  
pp. 1209-1217 ◽  
Author(s):  
Eric Lawitz ◽  
Maribel Rodriguez-Torres ◽  
Jill M. Denning ◽  
Efsevia Albanis ◽  
Melanie Cornpropst ◽  
...  
Keyword(s):  
Hepatitis C ◽  
Pharmacokinetic Profile ◽  
Hcv Rna ◽  
Hepatitis C Infection ◽  
Multiple Dosing ◽  
Double Blind ◽  
Time Curve ◽  
Dose Study ◽  
Treatment Naïve ◽  
Hcv Genotype 1

ABSTRACTWe conducted this double-blind, parallel-group, placebo-controlled, randomized, multiple-ascending-dose study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of GS-9851 (formerly PSI-7851) in treatment-naïve patients infected with hepatitis C virus (HCV) genotype 1. Thirty-two patients received active doses up to 400 mg of GS-9851 once daily for 3 days. GS-9851 and the metabolite GS-566500 (formerly PSI-352707) were rapidly cleared from the plasma, with half-life (t1/2) values of approximately 1 h for GS-9851 and 3 h for GS-566500. Accumulation (21%) was observed only for GS-331007 (formerly PSI-6206) after multiple dosing. GS-331007 was the primary drug-related moiety in the plasma and urine. Increases in the GS-9851, GS-566500, and GS-331007 maximum concentrations in plasma (Cmax) and area under the concentration-time curve (AUC) were less than dose proportional, particularly at the highest doses. The decline in plasma HCV RNA levels was dose dependent, and a mean maximal change from the baseline of −1.95 log10IU/ml was obtained for 400 mg GS-9851, compared with −0.090 log10IU/ml for the placebo. Most patients had a decrease in HCV RNA of ≥1.0 log10IU/ml after 3 days' dosing with 400 mg GS-9851. No virologic resistance was observed. GS-9851 was generally well tolerated, with no notable differences in adverse event frequency across doses. The pharmacokinetic profile observed in this study was similar to that seen in a single-ascending-dose study in healthy subjects.

scholarly journals Pharmacokinetics, Safety, and Tolerability of GS-9851, a Nucleotide Analog Polymerase Inhibitor for Hepatitis C Virus, following Single Ascending Doses in Healthy Subjects

2012 ◽  
Vol 57 (3) ◽  
pp. 1201-1208 ◽  
Author(s):  
Jill Denning ◽  
Melanie Cornpropst ◽  
Stephen D. Flach ◽  
Michelle M. Berrey ◽  
William T. Symonds
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Maximum Concentration ◽  
Healthy Subjects ◽  
Drug Exposure ◽  
Pharmacokinetic Profile ◽  
Maximum Tolerated Dose ◽  
Double Blind ◽  
Time Curve ◽  
Nucleotide Analog

ABSTRACTTo investigate the pharmacokinetics, safety, and tolerability of GS-9851 (formerly PSI-7851), a new nucleotide analog inhibitor of hepatitis C virus (HCV), we conducted a double-blind, parallel, placebo-controlled, randomized, single-ascending-dose study. Healthy subjects received oral doses of 25 to 800 mg GS-9851. Peak concentrations of GS-9851 in plasma were achieved more rapidly than those of the metabolites GS-566500 (formerly PSI-352707) and GS-331007 (formerly PSI-6206), with time to maximum concentration of drug in plasma (tmax) values of 1.0 to 1.8 h, 1.5 to 3.0 h, and 3.0 to 6.0 h, respectively. The majority of systemic drug exposure was from the nucleoside GS-331007, with maximum concentration of drug in plasma (Cmax) and area under the concentration-time curve to the last measurable concentration (AUC0–t) values at least 7- and 41-fold higher, respectively, than those obtained for GS-9851 after adjusting for differences in molecular weight. The terminal elimination half-life (t1/2) of GS-331007 increased with the dose, achieving at1/2of 25.7 h at 800 mg GS-9851. Dose proportionality was not observed for GS-331007. The majority of drug recovered in urine was in the form of GS-331007, with the percentage of this metabolite in urine samples ranging from 57% to 27% with increasing dose. GS-9851 was generally well tolerated, with no maximum tolerated dose identified. In conclusion, GS-9851 and its metabolites demonstrated a favorable pharmacokinetic profile consistent with once-daily dosing, and therefore, further clinical studies evaluating GS-9851 in HCV-infected patients are warranted.

EFFICACY OF SOFOSBUVIR AND DACLATASVIR IN COMPENSATED CHRONIC HEPATITIS C INFECTION: A SINGLE CENTER, OPEN-LABEL AND PROOF OF CONCEPT STUDY

2021 ◽  
pp. 27-30
Author(s):  
Manisha Thakur ◽  
Anurag Chauhan ◽  
Prashant Jambunathan ◽  
Shikha Awasthi ◽  
Thilagavathi K ◽  
...  
Keyword(s):  
Chronic Hepatitis ◽  
Hepatitis C ◽  
Sustained Virological Response ◽  
Chronic Hepatitis C ◽  
Virological Response ◽  
Sustained Viral Response ◽  
Hcv Rna ◽  
Hepatitis C Infection ◽  
Genotype 3 ◽  
Treatment Naïve

AIMS AND OBJECTIVES: The advent of directly acting agents for the treatment of Hepatitis C infection has forever transformed our understanding and management of viral infections. With over 95 % patients achieving a sustained viral response at 12 weeks with some of these newly inducted agents, the prospect of eradicating the Hepatitis C virus seems like an achievable target, which makes this one of the most important discoveries in modern medicine. We studied the combination of Sofosbuvir and Daclatasvir in patients with chronic hepatitis C infection (Genotype 3) to assess the rates of sustained virological response at 12 weeks. We studied 67 treatment naive METHODS: patients with compensated chronic hepatitis C infection (genotype 3). They were all started on Tab Sofosbuvir 400 mg daily and Tab Daclatasvir 60 mg once daily for 12 weeks and followed up for a total of 24 weeks, which includes a treatment duration and observation period of 12 weeks each. The patients were monitored with HCV RNA levels at one, three and six months, with as many evaluations of liver function and routine hemogram. Our results show that 70.5% (p<0.05) achieved a rapid vi RESULTS: rological response, 88.5% (p<0.05) achieved an end of treatment response and, similarly, an impressive 88.05% (p<0.05) showed a sustained virological response at the end of 12 weeks. One patient who developed a psoriasiform rash discontinued the medication and was excluded from the analysis, as duration of treatment had not been completed. No major dose related adverse events were reported. Sofosbuvir and Daclatasvir is an acceptable, well tolerated regimen for treatment naive, CONCLUSIONS: compensated patients with genotype 3 infection. Based on our observations and data, we recommend this as the rst line DAA for patient with compensated genotype 3 infection until medications with higher SVR 12 are available in the Indian market.

scholarly journals Antiviral Effect, Safety, and Pharmacokinetics of Five-Day Oral Administration of Deleobuvir (BI 207127), an Investigational Hepatitis C Virus RNA Polymerase Inhibitor, in Patients with Chronic Hepatitis C

2013 ◽  
Vol 57 (10) ◽  
pp. 4727-4735 ◽  
Author(s):  
Dominique Larrey ◽  
Ansgar W. Lohse ◽  
Christian Trepo ◽  
Jean-Pierre Bronowicki ◽  
Keikawus Arastéh ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antiviral Activity ◽  
Rna Polymerase ◽  
Hcv Rna ◽  
Genotype 1 ◽  
Double Blind ◽  
Hcv Genotype ◽  
Hcv Genotype 1 ◽  
Dose Dependent

ABSTRACTDeleobuvir (BI 207127) is an investigational oral nonnucleoside inhibitor of hepatitis C virus (HCV) NS5B RNA polymerase. Antiviral activity, virology, pharmacokinetics, and safety were assessed in HCV genotype 1-infected patients receiving 5 days' deleobuvir monotherapy. In this double-blind phase 1b study, treatment-naive (TN;n= 15) and treatment-experienced (TE;n= 45) patients without cirrhosis received placebo or deleobuvir at 100, 200, 400, 800, or 1,200 mg every 8 h (q8h) for 5 days. Patients with cirrhosis (n= 13) received deleobuvir at 400 or 600 mg q8h for 5 days. Virologic analyses included NS5B genotyping and phenotyping of individual isolates. At day 5, patients without cirrhosis had dose-dependent median HCV RNA reductions of up to 3.8 log10(with no placebo response); patients with cirrhosis had median HCV RNA reductions of approximately 3.0 log10. Three patients discontinued due to adverse events (AEs). The most common AEs were gastrointestinal, nervous system, and skin/cutaneous tissue disorders. Plasma exposure of deleobuvir was supraproportional at doses ≥ 400 mg q8h and approximately 2-fold higher in patients with cirrhosis than in patients without cirrhosis. No virologic breakthrough was observed. NS5B substitutions associated with deleobuvir resistancein vitrowere detected in 9/59 patients; seven encoded P495 substitutions, including P495L, which conferred 120- to 310-fold-decreased sensitivity to deleobuvir. P495 variants did not persist in follow-up without selective drug pressure. Deleobuvir monotherapy was generally well tolerated and demonstrated dose-dependent antiviral activity against HCV genotype 1 over 5 days.

scholarly journals Safety, Tolerability, and Pharmacokinetics of Oral Nafithromycin (WCK 4873) after Single or Multiple Doses and Effects of Food on Single-Dose Bioavailability in Healthy Adult Subjects

2019 ◽  
Vol 63 (12) ◽  
Author(s):  
Piotr Iwanowski ◽  
Ashima Bhatia ◽  
Mugdha Gupta ◽  
Anasuya Patel ◽  
Rajesh Chavan ◽  
...  
Keyword(s):  
Healthy Adult ◽  
Phase 1 ◽  
Human Study ◽  
Pharmacokinetic Profile ◽  
Maximum Plasma ◽  
Multiple Dosing ◽  
Double Blind ◽  
Time Curve ◽  
Dosing Regimens ◽  
Oral Doses

ABSTRACT Nafithromycin (WCK 4873), a novel lactone-ketolide, was administered to healthy adult subjects in 2 randomized, double-blind, placebo-controlled, phase 1 studies. In the first-in-human study, single ascending oral doses of nafithromycin (100 to 1,200 mg) were administered to subjects under fasted or fed conditions, with effects of food on bioavailability of nafithromycin studied at the dose levels of 400 and 800 mg. In the second study, multiple ascending oral doses of 600, 800, or 1,000 mg of nafithromycin were administered once daily for 7 days under fed conditions. Nafithromycin was generally well tolerated at all doses. No serious or severe adverse events were observed. The mean maximum plasma concentration (Cmax) ranged from 0.099 to 1.742 mg/liter, and the area under the concentration-time curve from time zero to time t (AUC0–t) ranged from 0.54 to 22.53 h·mg/liter. Nafithromycin plasma AUC0–t increased approximately 1.2-fold under fed compared to fasted conditions. In the multiple-dose study, the day 7 nafithromycin Cmax ranged from 1.340 to 2.987 mg/liter and the AUC over the final dosing interval (AUC0–24) ranged from 13.48 to 43.46 h·mg/liter. The steady state was achieved after 3 days for the 600-mg and 800-mg-dose cohorts and after 4 days for the 1,000-mg cohort. Under both single- and multiple-dosing regimens, plasma exposure to nafithromycin appeared to increase more than dose proportionally. Nafithromycin showed moderate accumulation on day 7 of dosing. The human pharmacokinetic profile, safety, and tolerability data support further development of nafithromycin. (This study has been registered at ClinicalTrials.gov under registration no. NCT03926962 and NCT03979859.)

scholarly journals Predictors of Response to 24-Week Telaprevir-Based Triple Therapy for Treatment-Naïve Genotype 1b Chronic Hepatitis C Patients

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Hiroshi Abe ◽  
Akihito Tsubota ◽  
Noritomo Shimada ◽  
Masanori Atsukawa ◽  
Keizo Kato ◽  
...  
Keyword(s):  
Hepatitis C ◽  
Virological Response ◽  
Multivariate Logistic Regression Analysis ◽  
Hcv Rna ◽  
Rapid Virological Response ◽  
Related Factors ◽  
Genotype 1B ◽  
Predictors Of Response ◽  
Treatment Naïve ◽  
Intent To Treat

We evaluated the genetic variation in rs8099917, substitutions in core amino acid (aa) 70, and the number of aa substitutions in the interferon sensitivity-determining region (ISDR) on the prediction of sustained virological response (SVR) in treatment-naïve hepatitis C virus (HCV) genotype 1b (G1b) patients. This multicenter study involved 150 Asian treatment-naïve patients infected with HCV G1b who received 12 weeks of telaprevir in combination with 24 weeks of peginterferon-α-2b and ribavirin. The baseline and treatment-related factors potentially associated with SVR were determined by multivariate logistic regression analysis. Virological response was analyzed on an intent-to-treat basis. Cessation of the therapy due to adverse effects occurred in only 2 patients, who discontinued the trial at 10 weeks and at 2 weeks due to cerebral infarction and renal impairment, respectively. Among the 150 patients in whom the final virological response was determined, only genotype TT in rs8099917 was identified as a pretreatment predictor (P= 7.38 × 10−4). Achievement of a rapid virological response (RVR), defined as undetectable HCV RNA at week 4 of treatment, was identified as an after-starting-treatment predictor (P= 2.47 × 10−5). However, neither a substitution in core aa 70 nor the number of substitutions in the ISDR affected treatment outcome.

scholarly journals In Vitro Activity and Preclinical Profile of TMC435350, a Potent Hepatitis C Virus Protease Inhibitor

2009 ◽  
Vol 53 (4) ◽  
pp. 1377-1385 ◽  
Author(s):  
Tse-I Lin ◽  
Oliver Lenz ◽  
Gregory Fanning ◽  
Thierry Verbinnen ◽  
Frédéric Delouvroy ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Intestinal Tract ◽  
Pharmacokinetic Profile ◽  
Absolute Bioavailability ◽  
Time Curve ◽  
Biochemical Assays ◽  
Single Oral Administration ◽  
Half Maximal Effective Concentration

ABSTRACT The hepatitis C virus (HCV) NS3/4A serine protease has been explored as a target for the inhibition of viral replication in preclinical models and in HCV-infected patients. TMC435350 is a highly specific and potent inhibitor of NS3/4A protease selected from a series of novel macrocyclic inhibitors. In biochemical assays using NS3/4A proteases of genotypes 1a and 1b, inhibition constants of 0.5 and 0.4 nM, respectively, were determined. TMC435350 inhibited HCV replication in a cellular assay (subgenomic 1b replicon) with a half-maximal effective concentration (EC50) of 8 nM and a selectivity index of 5,875. The compound was synergistic with alpha interferon and an NS5B inhibitor in the replicon model and additive with ribavirin. In rats, TMC435350 was extensively distributed to the liver and intestinal tract (tissue/plasma area under the concentration-time curve ratios of >35), and the absolute bioavailability was 44% after a single oral administration. Compound concentrations detected in both plasma and liver at 8 h postdosing were above the EC99 value measured in the replicon. In conclusion, given the selective and potent in vitro anti-HCV activity, the potential for combination with other anti-HCV agents, and the favorable pharmacokinetic profile, TMC435350 has been selected for clinical development.

scholarly journals Treatment of hepatitis C virus infection with direct-acting antiviral agent-based regimens in Iranian patients with hereditary bleeding disorders

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Heidar Sharafi ◽  
Bita Behnava ◽  
Alireza Azizi-saraji ◽  
Ali Namvar ◽  
Ali Anvar ◽  
...  
Keyword(s):  
Hepatitis C ◽  
Antiviral Agent ◽  
Previous Treatment ◽  
Virologic Response ◽  
Bleeding Disorders ◽  
Hcv Genotype ◽  
Direct Acting Antiviral ◽  
Treatment Naïve ◽  
Hcv Genotype 1 ◽  
Direct Acting

Abstract Background Chronic hepatitis C (CHC) is one of the most important comorbidities in patients with hereditary bleeding disorders (HBD). The present study aimed at evaluating the effectiveness of direct-acting antiviral agent (DAA)-based interferon-free HCV antiviral regimens in patients with HBD. Patients and methods The present study was performed on the patients with HBD and CHC between 2015 and 2019. Sofosbuvir-based interferon-free regimens with or without ribavirin were prescribed to treat HCV infection. The main endpoint of the study was to determine the sustained virologic response (SVR), assessed 12 weeks after the completion of treatment. Results A total of 147 patients with a mean age of 41.1 years were enrolled in the study; 4.1% of them were co-infected with HIV, 25.2% had cirrhosis, and 76.9% of them were diagnosed with hemophilia A. HCV genotype-1 includes the largest number (68.1%) of patients. 46.3% of patients were treatment-naïve and others had a treatment history with interferon-based regimens. Out of 147 patients, 15 patients were lost to follow-up during treatment or for SVR evaluation or discontinued treatment. 132 subjects completed treatment and were evaluated for SVR, 12 weeks after the completion of treatment. All of the patients achieved SVR 12 (SVR rate: 100%, 95% CI 97.2–100%). Conclusion Hepatitis C DAA-based regimens are the effective treatments for CHC in patients with HBD, regardless of the treatment modifiers such as previous treatment experience, cirrhosis, HIV co-infection, and HCV genotype.

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