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Diane R. Mould - One of the best experts on this subject based on the ideXlab platform.
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use of an indirect pharmacodynamic stimulation model of mx protein induction to compare in vivo activity of Interferon Alfa 2a and a polyethylene glycol modified derivative in healthy subjects
Clinical Pharmacology & Therapeutics, 1996Co-Authors: Keith Nieforth, Rosemary Nadeau, Indravadan H. Patel, Diane R. MouldAbstract:Interferon Alfa-2a was chemically modified by the covalent attachment of a polyethylene glycol (PEG) moiety to enhance its circulating half-life and to reduce its immunogenicity. A comparative evaluation of the pharmacokinetics of the PEG-modified Interferon Alfa-2a showed a greater than twofold increase in the circulating half-life as a result of this chemical modification. An indirect physiologic response model was developed to characterize the time course of the MX protein response after subcutaneous administration of single ascending doses of either Interferon Alfa-2a or PEG-Interferon Alfa-2a in healthy volunteers. Analysis of the pharmacokinetic-pharmacodynamic relationship suggested that the PEG-modified Interferon Alfa-2a could not be administered less than twice weekly and therefore offered little therapeutic advantage over its unmodified counterpart, which is administered three times weekly. These results were consistent with findings in phase II trials. This study substantiates the usefulness of pharmacodynamic modeling as a tool for the development of dose recommendations and for the early selection of drug candidates in the drug development process. Clinical Pharmacology & Therapeutics (1996) 59, 636–646; doi:
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use of an indirect pharmacodynamic stimulation model of mx protein induction to compare in vivo activity of Interferon Alfa 2a and a polyethylene glycol modified derivative in healthy subjects
Clinical Pharmacology & Therapeutics, 1996Co-Authors: Keith Nieforth, Rosemary Nadeau, Indravadan H. Patel, Diane R. MouldAbstract:Interferon Alfa-2a was chemically modified by the covalent attachment of a polyethylene glycol (PEG) moiety to enhance its circulating half-life and to reduce its immunogenicity. A comparative evaluation of the pharmacokinetics of the PEG-modified Interferon Alfa-2a showed a greater than twofold increase in the circulating half-life as a result of this chemical modification. An indirect physiologic response model was developed to characterize the time course of the MX protein response after subcutaneous administration of single ascending doses of either Interferon Alfa-2a or PEG-Interferon Alfa-2a in healthy volunteers. Analysis of the pharmacokinetic-pharmacodynamic relationship suggested that the PEG-modified Interferon Alfa-2a could not be administered less than twice weekly and therefore offered little therapeutic advantage over its unmodified counterpart, which is administered three times weekly. These results were consistent with findings in phase II trials. This study substantiates the usefulness of pharmacodynamic modeling as a tool for the development of dose recommendations and for the early selection of drug candidates in the drug development process.
Eugene R Schiff - One of the best experts on this subject based on the ideXlab platform.
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pegInterferon Alfa 2b and ribavirin effective in patients with hepatitis c who failed Interferon Alfa ribavirin therapy
Gastroenterology, 2009Co-Authors: Thierry Poynard, Eugene R Schiff, Jordi Bruix, Massimo Colombo, R Terg, Steven L Flamm, Ricardo Morenootero, Flair Jose Carrilho, W Schmidt, Thomas BergAbstract:Background & Aims Treatment with pegInterferon Alfa and ribavirin produces a sustained virologic response (SVR) in approximately 60% of hepatitis C virus (HCV)-infected patients. Alternate options are needed for patients who relapse or do not respond to therapy. Methods This prospective, international, multicenter, open-label study evaluated efficacy and safety of pegInterferon Alfa-2b (1.5 μg/kg/wk) plus weight-based ribavirin (800–1400 mg/day) in 2333 chronic HCV-infected patients with significant fibrosis/cirrhosis whose previous Interferon Alfa/ribavirin therapy failed. Patients with undetectable HCV-RNA at treatment week (TW) 12 received 48 weeks of therapy; patients with detectable HCV-RNA at TW12 could enter maintenance studies at TW18; 188 patients with low/detectable HCV-RNA at TW12 continued therapy at the investigator's request. Results Overall, 22% of the patients attained SVR (56% with undetectable HCV-RNA and 12% with low/detectable HCV-RNA at TW12). SVR was better in relapsers (38%) than nonresponders (14%), regardless of previous treatment, and in patients previously treated with Interferon-Alfa/ribavirin (25%) than pegInterferon Alfa-ribavirin (17%). Predictors of response in patients with undetectable HCV-RNA at TW12 were genotype (2/3 vs 1, respectively; odds ratio [OR] 2.4; P P 600,000 IU/mL; OR, 1.4; P = .0223). These factors plus previous treatment and response were overall predictors of SVR. Safety was similar among fibrosis groups. Conclusions PegInterferon Alfa-2b plus weight-based ribavirin is effective and safe in patients who failed Interferon Alfa/ribavirin therapy. Genotype, baseline viral load, and fibrosis stage were predictors of response.
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a randomized double blind trial comparing pegylated Interferon Alfa 2b to Interferon Alfa 2b as initial treatment for chronic hepatitis c
Hepatology, 2001Co-Authors: Karen L Lindsay, Mark A. Laughlin, Christian Trepo, Tobias Heintges, Stuart C. Gordon, John C. Hoefs, Mitchell L Shiffman, Eugene R Schiff, Zachary Goodman, Janice K AlbrechtAbstract:Abstract This international, randomized, active-controlled, parallel-group, double-blind dose-finding study compared pegInterferon Alfa-2b (PegIntron™) to Interferon Alfa-2b for the initial treatment of compensated chronic hepatitis C. We randomly assigned 1,219 subjects to receive either the standard three-times-weekly (TIW) Interferon Alfa-2b dose (3 MIU) or the once-weekly (QW) pegInterferon Alfa-2b (0.5, 1.0, or 1.5 μg/kg). Subjects were treated for 48 weeks and then followed for an additional 24 weeks. All 3 pegInterferon Alfa-2b doses significantly ( P ≤ .042) improved virologic response rates (loss of detectable serum HCV RNA) after treatment and after follow-up, as compared with Interferon Alfa-2b. Unlike the end-of-treatment virologic response, the sustained virologic response rate was not dose-related above 1.0 μg/kg pegInterferon Alfa-2b because of a higher relapse rate among patients treated with 1.5 μg/kg pegInterferon Alfa-2b, particularly among patients infected with genotype 1. All 3 pegInterferon Alfa-2b doses decreased liver inflammation to a greater extent than did Interferon Alfa-2b, particularly in subjects with sustained responses. No new adverse events were reported, and the majority of adverse events and changes in laboratory values were mild or moderate. In conclusion, pegInterferon Alfa-2b maintained (0.5 μg/kg) or surpassed (1.0, 1.5 μg/kg) the clinical efficacy of Interferon Alfa-2b while preserving its safety profile. The higher rate of virologic response during treatment with 1.5 μg/kg pegInterferon Alfa-2b in patients infected with genotype 1 and high viral levels warrants further evaluation. (H EPATOLOGY 2001;34:395-403.)
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a randomized double blind trial comparing pegylated Interferon Alfa 2b to Interferon Alfa 2b as initial treatment for chronic hepatitis c
Hepatology, 2001Co-Authors: Karen L Lindsay, Christian Trepo, Tobias Heintges, Stuart C. Gordon, John C. Hoefs, Mitchell L Shiffman, Eugene R Schiff, Zachary Goodman, Mark Laughlin, Ruji YaoAbstract:This international, randomized, active-controlled, parallel-group, double-blind dose-finding study compared pegInterferon Alfa-2b (PegIntron) to Interferon Alfa-2b for the initial treatment of compensated chronic hepatitis C. We randomly assigned 1,219 subjects to receive either the standard three-times-weekly (TIW) Interferon Alfa-2b dose (3 MIU) or the once-weekly (QW) pegInterferon Alfa-2b (0.5, 1.0, or 1.5 microg/kg). Subjects were treated for 48 weeks and then followed for an additional 24 weeks. All 3 pegInterferon Alfa-2b doses significantly (P < or =.042) improved virologic response rates (loss of detectable serum HCV RNA) after treatment and after follow-up, as compared with Interferon Alfa-2b. Unlike the end-of-treatment virologic response, the sustained virologic response rate was not dose-related above 1.0 microg/kg pegInterferon Alfa-2b because of a higher relapse rate among patients treated with 1.5 microg/kg pegInterferon Alfa-2b, particularly among patients infected with genotype 1. All 3 pegInterferon Alfa-2b doses decreased liver inflammation to a greater extent than did Interferon Alfa-2b, particularly in subjects with sustained responses. No new adverse events were reported, and the majority of adverse events and changes in laboratory values were mild or moderate. In conclusion, pegInterferon Alfa-2b maintained (0.5 microg/kg) or surpassed (1.0, 1.5 microg/kg) the clinical efficacy of Interferon Alfa-2b while preserving its safety profile. The higher rate of virologic response during treatment with 1.5 microg/kg pegInterferon Alfa-2b in patients infected with genotype 1 and high viral levels warrants further evaluation.
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Interferon Alfa 2b alone or in combination with ribavirin as initial treatment for chronic hepatitis c
The New England Journal of Medicine, 1998Co-Authors: John G Mchutchison, Meihsiu Ling, Vinod K Rustgi, Stuart C. Gordon, Eugene R Schiff, Zachary Goodman, Susannah Cort, Janice K AlbrechtAbstract:Background Only 15 to 20 percent of patients with chronic hepatitis C have a sustained virologic response to Interferon therapy. We compared the efficacy and safety of recombinant Interferon Alfa-2b alone with those of a combination of Interferon Alfa-2b and ribavirin for the initial treatment of patients with chronic hepatitis C. Methods We randomly assigned 912 patients with chronic hepatitis C to receive standard-dose Interferon Alfa-2b alone or in combination with ribavirin (1000 or 1200 mg orally per day, depending on body weight) for 24 or 48 weeks. Efficacy was assessed by measurements of serum hepatitis C virus (HCV) RNA and serum aminotransferases and by liver biopsy. Results The rate of sustained virologic response (defined as an undetectable serum HCV RNA level 24 weeks after treatment was completed) was higher among patients who received combination therapy for either 24 weeks (70 of 228 patients, 31 percent) or 48 weeks (87 of 228 patients, 38 percent) than among patients who received interfe...
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hepatic iron concentration as a predictor of response to Interferon Alfa therapy in chronic hepatitis c
Gastroenterology, 1995Co-Authors: John K Olynyk, Adrian M. Di Bisceglie, Eugene R Schiff, Rajender K Reddy, Lennox J Jeffers, Talley Parker, Jason L Radick, Bruce R BaconAbstract:Background/Aims: It has been reported that hepatic iron concentration (HIC) may influence response to therapy in chronic viral hepatitis. The aim of this study was to determine the relationship between HIC and response to Interferon Alfa therapy in patients with chronic hepatitis C. Methods: HIC was measured in liver biopsy specimens from 58 patients with chronic hepatitis C treated at three centers. Three patients had mild chronic hepatitis C, 35 had moderate to severe chronic hepatitis C, and 20 had active cirrhosis. Serum ferritin levels were measured in 51 of these 58 patients. Response to therapy was defined as normalization of alanine aminotransferase levels at the end of treatment. Results: Twenty-four patients (41%) responded to therapy. HICs were generally within the normal range ( 1100 μg/g and 87% of patients with an elevated serum ferritin concentration did not respond to Interferon Alfa therapy. Conclusions: HIC seems to influence response to Interferon Alfa therapy among patients with chronic hepatitis C. A subgroup of patients with chronic hepatitis C has been identified for which an HIC of >1100 μg/g predicted nonresponse in 88% of patients.
Caroline Robert - One of the best experts on this subject based on the ideXlab platform.
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long term results of the randomized phase iii trial eortc 18991 of adjuvant therapy with pegylated Interferon Alfa 2b versus observation in resected stage iii melanoma
Journal of Clinical Oncology, 2012Co-Authors: Alexander M M Eggermont, Stefan Suciu, Mario Santinami, Alessandro Testori, Wim H J Kruit, J Marsden, Cornelis J A Punt, Francois Sales, Reinhard Dummer, Caroline RobertAbstract:Purpose Adjuvant pegylated Interferon Alfa-2b (PEG-IFN--2b) was approved for treatment of resected stage III melanoma in 2011. Here, we present long-term follow-up results of this pivotal trial.
Keith Nieforth - One of the best experts on this subject based on the ideXlab platform.
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use of an indirect pharmacodynamic stimulation model of mx protein induction to compare in vivo activity of Interferon Alfa 2a and a polyethylene glycol modified derivative in healthy subjects
Clinical Pharmacology & Therapeutics, 1996Co-Authors: Keith Nieforth, Rosemary Nadeau, Indravadan H. Patel, Diane R. MouldAbstract:Interferon Alfa-2a was chemically modified by the covalent attachment of a polyethylene glycol (PEG) moiety to enhance its circulating half-life and to reduce its immunogenicity. A comparative evaluation of the pharmacokinetics of the PEG-modified Interferon Alfa-2a showed a greater than twofold increase in the circulating half-life as a result of this chemical modification. An indirect physiologic response model was developed to characterize the time course of the MX protein response after subcutaneous administration of single ascending doses of either Interferon Alfa-2a or PEG-Interferon Alfa-2a in healthy volunteers. Analysis of the pharmacokinetic-pharmacodynamic relationship suggested that the PEG-modified Interferon Alfa-2a could not be administered less than twice weekly and therefore offered little therapeutic advantage over its unmodified counterpart, which is administered three times weekly. These results were consistent with findings in phase II trials. This study substantiates the usefulness of pharmacodynamic modeling as a tool for the development of dose recommendations and for the early selection of drug candidates in the drug development process. Clinical Pharmacology & Therapeutics (1996) 59, 636–646; doi:
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use of an indirect pharmacodynamic stimulation model of mx protein induction to compare in vivo activity of Interferon Alfa 2a and a polyethylene glycol modified derivative in healthy subjects
Clinical Pharmacology & Therapeutics, 1996Co-Authors: Keith Nieforth, Rosemary Nadeau, Indravadan H. Patel, Diane R. MouldAbstract:Interferon Alfa-2a was chemically modified by the covalent attachment of a polyethylene glycol (PEG) moiety to enhance its circulating half-life and to reduce its immunogenicity. A comparative evaluation of the pharmacokinetics of the PEG-modified Interferon Alfa-2a showed a greater than twofold increase in the circulating half-life as a result of this chemical modification. An indirect physiologic response model was developed to characterize the time course of the MX protein response after subcutaneous administration of single ascending doses of either Interferon Alfa-2a or PEG-Interferon Alfa-2a in healthy volunteers. Analysis of the pharmacokinetic-pharmacodynamic relationship suggested that the PEG-modified Interferon Alfa-2a could not be administered less than twice weekly and therefore offered little therapeutic advantage over its unmodified counterpart, which is administered three times weekly. These results were consistent with findings in phase II trials. This study substantiates the usefulness of pharmacodynamic modeling as a tool for the development of dose recommendations and for the early selection of drug candidates in the drug development process.
Alexander M M Eggermont - One of the best experts on this subject based on the ideXlab platform.
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long term results of the randomized phase iii trial eortc 18991 of adjuvant therapy with pegylated Interferon Alfa 2b versus observation in resected stage iii melanoma
Journal of Clinical Oncology, 2012Co-Authors: Alexander M M Eggermont, Stefan Suciu, Mario Santinami, Alessandro Testori, Wim H J Kruit, J Marsden, Cornelis J A Punt, Francois Sales, Reinhard Dummer, Caroline RobertAbstract:Purpose Adjuvant pegylated Interferon Alfa-2b (PEG-IFN--2b) was approved for treatment of resected stage III melanoma in 2011. Here, we present long-term follow-up results of this pivotal trial.
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adjuvant therapy with pegylated Interferon Alfa 2b versus observation alone in resected stage iii melanoma final results of eortc 18991 a randomised phase iii trial
The Lancet, 2008Co-Authors: Alexander M M Eggermont, Stefan Suciu, Mario Santinami, Alessandro Testori, Wim H J Kruit, J Marsden, Cornelis J A Punt, Francois Sales, Martin Gore, Rona MackieAbstract:BACKGROUND: Any benefit of adjuvant Interferon Alfa-2b for melanoma could depend on dose and duration of treatment. Our aim was to determine whether pegylated Interferon Alfa-2b can facilitate prolonged exposure while maintaining tolerability. METHODS: 1256 patients with resected stage III melanoma were randomly assigned to observation (n=629) or pegylated Interferon Alfa-2b (n=627) 6 mug/kg per week for 8 weeks (induction) then 3 mug/kg per week (maintenance) for an intended duration of 5 years. Randomisation was stratified for microscopic (N1) versus macroscopic (N2) nodal involvement, number of positive nodes, ulceration and tumour thickness, sex, and centre. Randomisation was done with a minimisation technique. The primary endpoint was recurrence-free survival. Analyses were done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00006249. FINDINGS: All randomised patients were included in the primary efficacy analysis. 608 patients in the Interferon group and 613 patients in the observation group were included in safety analyses. The median length of treatment with pegylated Interferon Alfa-2b was 12 (IQR 3.8-33.4) months. At 3.8 (3.2-4.2) years median follow-up, 328 recurrence events had occurred in the Interferon group compared with 368 in the observation group (hazard ratio 0.82, 95% CI 0.71-0.96; p=0.01); the 4-year rate of recurrence-free survival was 45.6% (SE 2.2) in the Interferon group and 38.9% (2.2) in the observation group. There was no difference in overall survival between the groups. Grade 3 adverse events occurred in 246 (40%) patients in the Interferon group and 60 (10%) in the observation group; grade 4 adverse events occurred in 32 (5%) patients in the Interferon group and 14 (2%) in the observation group. In the Interferon group, the most common grade 3 or 4 adverse events were fatigue (97 patients, 16%), hepatotoxicity (66, 11%), and depression (39, 6%). Treatment with pegylated Interferon Alfa-2b was discontinued because of toxicity in 191 (31%) patients. INTERPRETATION: Adjuvant pegylated Interferon Alfa-2b for stage III melanoma has a significant, sustained effect on recurrence-free survival.
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adjuvant therapy with pegylated Interferon Alfa 2b versus observation alone in resected stage iii melanoma final results of eortc 18991 a randomised phase iii trial
The Lancet, 2008Co-Authors: Alexander M M Eggermont, Stefan Suciu, Mario Santinami, Alessandro Testori, Wim H J Kruit, J Marsden, Cornelis J A Punt, Francois Sales, Martin Gore, Rona MackieAbstract:Summary Background Any benefit of adjuvant Interferon Alfa-2b for melanoma could depend on dose and duration of treatment. Our aim was to determine whether pegylated Interferon Alfa-2b can facilitate prolonged exposure while maintaining tolerability. Methods 1256 patients with resected stage III melanoma were randomly assigned to observation (n=629) or pegylated Interferon Alfa-2b (n=627) 6 μg/kg per week for 8 weeks (induction) then 3 μg/kg per week (maintenance) for an intended duration of 5 years. Randomisation was stratified for microscopic (N1) versus macroscopic (N2) nodal involvement, number of positive nodes, ulceration and tumour thickness, sex, and centre. Randomisation was done with a minimisation technique. The primary endpoint was recurrence-free survival. Analyses were done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00006249. Findings All randomised patients were included in the primary efficacy analysis. 608 patients in the Interferon group and 613 patients in the observation group were included in safety analyses. The median length of treatment with pegylated Interferon Alfa-2b was 12 (IQR 3·8–33·4) months. At 3·8 (3·2–4·2) years median follow-up, 328 recurrence events had occurred in the Interferon group compared with 368 in the observation group (hazard ratio 0·82, 95% CI 0·71–0·96; p=0·01); the 4-year rate of recurrence-free survival was 45·6% (SE 2·2) in the Interferon group and 38·9% (2·2) in the observation group. There was no difference in overall survival between the groups. Grade 3 adverse events occurred in 246 (40%) patients in the Interferon group and 60 (10%) in the observation group; grade 4 adverse events occurred in 32 (5%) patients in the Interferon group and 14 (2%) in the observation group. In the Interferon group, the most common grade 3 or 4 adverse events were fatigue (97 patients, 16%), hepatotoxicity (66, 11%), and depression (39, 6%). Treatment with pegylated Interferon Alfa-2b was discontinued because of toxicity in 191 (31%) patients. Interpretation Adjuvant pegylated Interferon Alfa-2b for stage III melanoma has a significant, sustained effect on recurrence-free survival. Funding Schering Plough Research International.