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Omar Vesga - One of the best experts on this subject based on the ideXlab platform.
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Demonstration of Therapeutic Equivalence of Fluconazole Generic Products in the Neutropenic Mouse Model of Disseminated Candidiasis
PloS one, 2015Co-Authors: Javier Martínez González, Andres F. Zuluaga, Maria Agudelo, Carlos A. Rodriguez, Omar VesgaAbstract:Some generics of antibacterials fail Therapeutic Equivalence despite being pharmaceutical equivalents of their innovators, but data are scarce with antifungals. We used the neutropenic mice model of disseminated candidiasis to challenge the Therapeutic Equivalence of three generic products of fluconazole compared with the innovator in terms of concentration of the active pharmaceutical ingredient, analytical chemistry (liquid chromatography/mass spectrometry), in vitro susceptibility testing, single-dose serum pharmacokinetics in infected mice, and in vivo pharmacodynamics. Neutropenic, five week-old, murine pathogen free male mice of the strain Udea:ICR(CD-2) were injected in the tail vein with Candida albicans GRP-0144 (MIC = 0.25 mg/L) or Candida albicans CIB-19177 (MIC = 4 mg/L). Subcutaneous therapy with fluconazole (generics or innovator) and sterile saline (untreated controls) started 2 h after infection and ended 24 h later, with doses ranging from no effect to maximal effect (1 to 128 mg/kg per day) divided every 3 or 6 hours. The Hill’s model was fitted to the data by nonlinear regression, and results from each group compared by curve fitting analysis. All products were identical in terms of concentration, chromatographic and spectrographic profiles, MICs, mouse pharmacokinetics, and in vivo pharmacodynamic parameters. In conclusion, the generic products studied were pharmaceutically and Therapeutically equivalent to the innovator of fluconazole.
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relevance of various animal models of human infections to establish Therapeutic Equivalence of a generic product of piperacillin tazobactam
International Journal of Antimicrobial Agents, 2015Co-Authors: Maria Agudelo, Andres F. Zuluaga, Carlos A. Rodriguez, Omar VesgaAbstract:After demonstrating with diverse intravenous antibacterials that pharmaceutical Equivalence (PE) does not predict Therapeutic Equivalence, we tested a single generic product of piperacillin/tazobactam (TZP) in terms of PE, pharmacokinetics and in vitro/vivo pharmacodynamics against several pathogens in neutropenic mouse thigh, lung and brain infection models. A generic product was compared head-to-head against the innovator. PE was evaluated by microbiological assay. Single-dose serum pharmacokinetics were determined in infected mice, and the MIC/MBC were determined by broth microdilution. In vivo experiments were done in a blind fashion. Reproducibility was tested on different days using different infecting organisms and animal models. Neutropenic MPF mice were infected in the thighs with Staphylococcus aureus GRP-0057 or Pseudomonas aeruginosa PA01 and in the lungs or brain with Klebsiella pneumoniae ATCC 10031. Treatment started 2h (thigh and brain) or 14 h (lung) after infection and was administered every 3h over 24h (thigh and lung) or 48 h (brain). Both products exhibited the same MIC/MBC against each strain, yielded overlaid curves in the microbiological assay (P>0.21) and were bioequivalent (IC90 83-117% for AUC test/reference ratio). In vivo, the generic product and innovator were again undistinguishable in all models and against the different bacterial pathogens involved. The relevance of these neutropenic murine models of infection was established by demonstrating their accuracy to predict the biological response following simultaneous treatment with a generic product or the innovator of TZP. Therapeutic Equivalence of the generic product was proved in every model and against different pathogens.
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Relevance of various animal models of human infections to establish Therapeutic Equivalence of a generic product of piperacillin/tazobactam
International journal of antimicrobial agents, 2014Co-Authors: Maria Agudelo, Andres F. Zuluaga, Carlos A. Rodriguez, Omar VesgaAbstract:After demonstrating with diverse intravenous antibacterials that pharmaceutical Equivalence (PE) does not predict Therapeutic Equivalence, we tested a single generic product of piperacillin/tazobactam (TZP) in terms of PE, pharmacokinetics and in vitro/vivo pharmacodynamics against several pathogens in neutropenic mouse thigh, lung and brain infection models. A generic product was compared head-to-head against the innovator. PE was evaluated by microbiological assay. Single-dose serum pharmacokinetics were determined in infected mice, and the MIC/MBC were determined by broth microdilution. In vivo experiments were done in a blind fashion. Reproducibility was tested on different days using different infecting organisms and animal models. Neutropenic MPF mice were infected in the thighs with Staphylococcus aureus GRP-0057 or Pseudomonas aeruginosa PA01 and in the lungs or brain with Klebsiella pneumoniae ATCC 10031. Treatment started 2h (thigh and brain) or 14 h (lung) after infection and was administered every 3h over 24h (thigh and lung) or 48 h (brain). Both products exhibited the same MIC/MBC against each strain, yielded overlaid curves in the microbiological assay (P>0.21) and were bioequivalent (IC90 83-117% for AUC test/reference ratio). In vivo, the generic product and innovator were again undistinguishable in all models and against the different bacterial pathogens involved. The relevance of these neutropenic murine models of infection was established by demonstrating their accuracy to predict the biological response following simultaneous treatment with a generic product or the innovator of TZP. Therapeutic Equivalence of the generic product was proved in every model and against different pathogens.
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Therapeutic Equivalence requires pharmaceutical pharmacokinetic and pharmacodynamic identities true bioEquivalence of a generic product of intravenous metronidazole
Antimicrobial Agents and Chemotherapy, 2012Co-Authors: Maria Agudelo, Omar VesgaAbstract:Animal models of infection have been used to demonstrate the Therapeutic failure of “bioequivalent” generic products, but their applicability for this purpose requires the accurate identification of those products that are truly bioequivalent. Here, we present data comparing one intravenous generic product of metronidazole with the innovator product in a neutropenic mouse thigh anaerobic infection model. Simultaneous experiments allowed comparisons (generic versus innovator) of potency and the concentration of the active pharmaceutical ingredient (API), analytical chemistry (liquid chromatography/mass spectrometry [LC/MS]), in vitro susceptibility testing, single-dose serum pharmacokinetics (PK) in infected mice, and in vivo pharmacodynamics (PD) against Bacteroides fragilis ATCC 25825 in synergy with Escherichia coli SIG-1 in the neutropenic mouse thigh anaerobic infection model. The Hill dose-response model followed by curve-fitting analysis was used to calculate and compare primary and secondary PD parameters. The generic and the innovator products were identical in terms of the concentration and potency of the API, chromatographic and spectrographic profiles, MIC and minimal bactericidal concentrations (MBC) (2.0 mg/liter), and mouse PK. We found no differences between products in bacteriostatic doses (BD) (15 to 22 mg/kg of body weight per day) or the doses needed to kill 1 log (1LKD) (21 to 29 mg/kg per day) or 2 logs (2LKD) (28 to 54 mg/kg per day) of B. fragilis under dosing schedules of every 12 h (q12h), q8h, or q6h. The area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC ratio) was the best PD index to predict the antibacterial efficacy of metronidazole (adjusted coefficient of determination [AdjR2] = 84.6%), and its magnitude to reach bacteriostasis in vivo (56.6 ± 5.17 h) or to kill the first (90.8 ± 9.78 h) and second (155.5 ± 22.2 h) logs was the same for both products. Animal models of infection allow a thorough demonstration of the Therapeutic Equivalence of generic antimicrobials.
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Determination of Therapeutic Equivalence of Generic Products of Gentamicin in the Neutropenic Mouse Thigh Infection Model
PloS one, 2010Co-Authors: Andres F. Zuluaga, Maria Agudelo, John J. Cardeño, Carlos A. Rodriguez, Omar VesgaAbstract:Background Drug regulatory agencies (DRA) support prescription of generic products of intravenous antibiotics assuming Therapeutic Equivalence from pharmaceutical Equivalence. Recent reports of deaths associated with generic heparin and metoprolol have raised concerns about the efficacy and safety of DRA-approved drugs. Methodology/Principal Findings To challenge the assumption that pharmaceutical Equivalence predicts Therapeutic Equivalence, we determined in vitro and in vivo the efficacy of the innovator product and 20 pharmaceutically equivalent generics of gentamicin. The data showed that, while only 1 generic product failed in vitro (MIC = 45.3 vs. 0.7 mg/L, P
Marie Carlholm - One of the best experts on this subject based on the ideXlab platform.
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methacholine challenge tests to demonstrate Therapeutic Equivalence of terbutaline sulfate via different turbuhaler devices in patients with mild to moderate asthma appraisal of a four way crossover design
Pulmonary Pharmacology & Therapeutics, 2017Co-Authors: Leif Bjermer, Jonas Román, Tore Persson, Gail M Gauvreau, Dirkje S Postma, Paul M Obyrne, Maarten Van Den Berge, Louis Philippe Boulet, Ola Beckman, Marie CarlholmAbstract:Background/Objective To demonstrate Therapeutic Equivalence of terbutaline via two different Turbuhaler® devices by evaluating its protective effect against methacholine-induced bronchoconstriction in stable asthma. Methods In this double-blind, double-dummy, multicentre, single-dose, 4-way crossover study, patients with stable mild-to-moderate asthma (FEV1 ≥80% predicted) were randomised to 0.5 or 1.5 mg terbutaline via either Turbuhaler® M2 or Turbuhaler® M3 followed by a methacholine challenge test. The primary outcome variable was the concentration of methacholine causing a 20% drop in FEV1 (PC20). Patients had a PC20 methacholine <8 mg/mL that was reproducible after 2 weeks, and a stable baseline FEV1 at all visits (90–110% of enrolment value). Results 60 patients (mean age 31.1 years [range:18–64]; mean FEV1 92.1% predicted normal [78.4–120.6%]) were randomised to treatment; all completed the study. There was a clear dose–response for both devices. The within-device ratios (1.5 mg:0.5 mg) were 1.79 and 1.87 for Turbuhaler® M3 and M2, respectively (both p < 0.001). The between-device ratios (M3:M2) were 0.92 (95% CI: 0.75–1.13) for 0.5 mg and 0.88 (95% CI 0.72–1.08) for 1.5 mg. Both confidence intervals lie inside the interval 0.67–1.50, which was the pre-specified condition for equivalent effect. Conclusions Bronchoprotection using a standardised methacholine challenge model proved to be an effective design to elucidate Therapeutic Equivalence between devices in patients with mild-to-moderate asthma. The findings indicate that patients may switch from one type of Turbuhaler® to the other without adjustment of therapy. Moreover, they show the robustness and utility of this study design and its suitability for investigating Therapeutic Equivalence. EudraCT Number 2014-001457-16. Clinicaltrials.gov identifier NCT02322788. (Less)
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Methacholine challenge tests to demonstrate Therapeutic Equivalence of terbutaline sulfate via different Turbuhaler® devices in patients with mild to moderate asthma: Appraisal of a four-way crossover design.
Pulmonary pharmacology & therapeutics, 2017Co-Authors: Leif Bjermer, Jonas Román, Tore Persson, Gail M Gauvreau, Dirkje S Postma, Louis Philippe Boulet, Ola Beckman, Paul M. O'byrne, M. Van Den Berge, Marie CarlholmAbstract:Background/Objective To demonstrate Therapeutic Equivalence of terbutaline via two different Turbuhaler® devices by evaluating its protective effect against methacholine-induced bronchoconstriction in stable asthma. Methods In this double-blind, double-dummy, multicentre, single-dose, 4-way crossover study, patients with stable mild-to-moderate asthma (FEV1 ≥80% predicted) were randomised to 0.5 or 1.5 mg terbutaline via either Turbuhaler® M2 or Turbuhaler® M3 followed by a methacholine challenge test. The primary outcome variable was the concentration of methacholine causing a 20% drop in FEV1 (PC20). Patients had a PC20 methacholine
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P134 Methacholine challenge to demonstrate Therapeutic Equivalence of terbutaline via different turbuhaler devices in patients with mild to moderate asthma: appraisal of a phase iii, four-way crossover design
Thorax, 2016Co-Authors: Leif Bjermer, Jonas Román, Tore Persson, Gail M Gauvreau, Dirkje S Postma, Louis Philippe Boulet, Ola Beckman, Paul M. O'byrne, M. Van Den Berge, Marie CarlholmAbstract:Background/objective To demonstrate Therapeutic Equivalence of terbutaline via two different Turbuhaler® devices by evaluating its protective effect against methacholine-induced bronchoconstriction in patients with stable asthma. Methods In this double-blind, double-dummy, multicentre, single-dose, 4-way crossover study, patients with stable, mild-to-moderate asthma (FEV1 ≥ 80% predicted normal) were randomised to 0.5 or 1.5 mg terbutaline via either Turbuhaler® M3 or M2 followed by a methacholine challenge test. Primary outcome variable: concentration of methacholine causing a 20% drop in FEV1 (PC20). Patients had to have a PC20 methacholine Results 60 patients were randomised to treatment and completed the study. There was a clear dose–response for both devices. The within-device ratios (1.5 mg: 0.5 mg) were 1.79 and 1.87 for Turbuhaler M3 and M2, respectively (both p Conclusions Bronchoprotection with PC20 as the outcome measure in a standardised methacholine challenge model proved to be a useful design to show Therapeutic Equivalence between devices in patients with mild to moderate asthma. This model provides robust reproducible data, involves smaller patient numbers with fewer dropouts resulting in reduced costs versus a conventional efficacy study.
Maria Agudelo - One of the best experts on this subject based on the ideXlab platform.
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Demonstration of Therapeutic Equivalence of Fluconazole Generic Products in the Neutropenic Mouse Model of Disseminated Candidiasis
PloS one, 2015Co-Authors: Javier Martínez González, Andres F. Zuluaga, Maria Agudelo, Carlos A. Rodriguez, Omar VesgaAbstract:Some generics of antibacterials fail Therapeutic Equivalence despite being pharmaceutical equivalents of their innovators, but data are scarce with antifungals. We used the neutropenic mice model of disseminated candidiasis to challenge the Therapeutic Equivalence of three generic products of fluconazole compared with the innovator in terms of concentration of the active pharmaceutical ingredient, analytical chemistry (liquid chromatography/mass spectrometry), in vitro susceptibility testing, single-dose serum pharmacokinetics in infected mice, and in vivo pharmacodynamics. Neutropenic, five week-old, murine pathogen free male mice of the strain Udea:ICR(CD-2) were injected in the tail vein with Candida albicans GRP-0144 (MIC = 0.25 mg/L) or Candida albicans CIB-19177 (MIC = 4 mg/L). Subcutaneous therapy with fluconazole (generics or innovator) and sterile saline (untreated controls) started 2 h after infection and ended 24 h later, with doses ranging from no effect to maximal effect (1 to 128 mg/kg per day) divided every 3 or 6 hours. The Hill’s model was fitted to the data by nonlinear regression, and results from each group compared by curve fitting analysis. All products were identical in terms of concentration, chromatographic and spectrographic profiles, MICs, mouse pharmacokinetics, and in vivo pharmacodynamic parameters. In conclusion, the generic products studied were pharmaceutically and Therapeutically equivalent to the innovator of fluconazole.
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relevance of various animal models of human infections to establish Therapeutic Equivalence of a generic product of piperacillin tazobactam
International Journal of Antimicrobial Agents, 2015Co-Authors: Maria Agudelo, Andres F. Zuluaga, Carlos A. Rodriguez, Omar VesgaAbstract:After demonstrating with diverse intravenous antibacterials that pharmaceutical Equivalence (PE) does not predict Therapeutic Equivalence, we tested a single generic product of piperacillin/tazobactam (TZP) in terms of PE, pharmacokinetics and in vitro/vivo pharmacodynamics against several pathogens in neutropenic mouse thigh, lung and brain infection models. A generic product was compared head-to-head against the innovator. PE was evaluated by microbiological assay. Single-dose serum pharmacokinetics were determined in infected mice, and the MIC/MBC were determined by broth microdilution. In vivo experiments were done in a blind fashion. Reproducibility was tested on different days using different infecting organisms and animal models. Neutropenic MPF mice were infected in the thighs with Staphylococcus aureus GRP-0057 or Pseudomonas aeruginosa PA01 and in the lungs or brain with Klebsiella pneumoniae ATCC 10031. Treatment started 2h (thigh and brain) or 14 h (lung) after infection and was administered every 3h over 24h (thigh and lung) or 48 h (brain). Both products exhibited the same MIC/MBC against each strain, yielded overlaid curves in the microbiological assay (P>0.21) and were bioequivalent (IC90 83-117% for AUC test/reference ratio). In vivo, the generic product and innovator were again undistinguishable in all models and against the different bacterial pathogens involved. The relevance of these neutropenic murine models of infection was established by demonstrating their accuracy to predict the biological response following simultaneous treatment with a generic product or the innovator of TZP. Therapeutic Equivalence of the generic product was proved in every model and against different pathogens.
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Relevance of various animal models of human infections to establish Therapeutic Equivalence of a generic product of piperacillin/tazobactam
International journal of antimicrobial agents, 2014Co-Authors: Maria Agudelo, Andres F. Zuluaga, Carlos A. Rodriguez, Omar VesgaAbstract:After demonstrating with diverse intravenous antibacterials that pharmaceutical Equivalence (PE) does not predict Therapeutic Equivalence, we tested a single generic product of piperacillin/tazobactam (TZP) in terms of PE, pharmacokinetics and in vitro/vivo pharmacodynamics against several pathogens in neutropenic mouse thigh, lung and brain infection models. A generic product was compared head-to-head against the innovator. PE was evaluated by microbiological assay. Single-dose serum pharmacokinetics were determined in infected mice, and the MIC/MBC were determined by broth microdilution. In vivo experiments were done in a blind fashion. Reproducibility was tested on different days using different infecting organisms and animal models. Neutropenic MPF mice were infected in the thighs with Staphylococcus aureus GRP-0057 or Pseudomonas aeruginosa PA01 and in the lungs or brain with Klebsiella pneumoniae ATCC 10031. Treatment started 2h (thigh and brain) or 14 h (lung) after infection and was administered every 3h over 24h (thigh and lung) or 48 h (brain). Both products exhibited the same MIC/MBC against each strain, yielded overlaid curves in the microbiological assay (P>0.21) and were bioequivalent (IC90 83-117% for AUC test/reference ratio). In vivo, the generic product and innovator were again undistinguishable in all models and against the different bacterial pathogens involved. The relevance of these neutropenic murine models of infection was established by demonstrating their accuracy to predict the biological response following simultaneous treatment with a generic product or the innovator of TZP. Therapeutic Equivalence of the generic product was proved in every model and against different pathogens.
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Therapeutic Equivalence requires pharmaceutical pharmacokinetic and pharmacodynamic identities true bioEquivalence of a generic product of intravenous metronidazole
Antimicrobial Agents and Chemotherapy, 2012Co-Authors: Maria Agudelo, Omar VesgaAbstract:Animal models of infection have been used to demonstrate the Therapeutic failure of “bioequivalent” generic products, but their applicability for this purpose requires the accurate identification of those products that are truly bioequivalent. Here, we present data comparing one intravenous generic product of metronidazole with the innovator product in a neutropenic mouse thigh anaerobic infection model. Simultaneous experiments allowed comparisons (generic versus innovator) of potency and the concentration of the active pharmaceutical ingredient (API), analytical chemistry (liquid chromatography/mass spectrometry [LC/MS]), in vitro susceptibility testing, single-dose serum pharmacokinetics (PK) in infected mice, and in vivo pharmacodynamics (PD) against Bacteroides fragilis ATCC 25825 in synergy with Escherichia coli SIG-1 in the neutropenic mouse thigh anaerobic infection model. The Hill dose-response model followed by curve-fitting analysis was used to calculate and compare primary and secondary PD parameters. The generic and the innovator products were identical in terms of the concentration and potency of the API, chromatographic and spectrographic profiles, MIC and minimal bactericidal concentrations (MBC) (2.0 mg/liter), and mouse PK. We found no differences between products in bacteriostatic doses (BD) (15 to 22 mg/kg of body weight per day) or the doses needed to kill 1 log (1LKD) (21 to 29 mg/kg per day) or 2 logs (2LKD) (28 to 54 mg/kg per day) of B. fragilis under dosing schedules of every 12 h (q12h), q8h, or q6h. The area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC ratio) was the best PD index to predict the antibacterial efficacy of metronidazole (adjusted coefficient of determination [AdjR2] = 84.6%), and its magnitude to reach bacteriostasis in vivo (56.6 ± 5.17 h) or to kill the first (90.8 ± 9.78 h) and second (155.5 ± 22.2 h) logs was the same for both products. Animal models of infection allow a thorough demonstration of the Therapeutic Equivalence of generic antimicrobials.
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Determination of Therapeutic Equivalence of Generic Products of Gentamicin in the Neutropenic Mouse Thigh Infection Model
PloS one, 2010Co-Authors: Andres F. Zuluaga, Maria Agudelo, John J. Cardeño, Carlos A. Rodriguez, Omar VesgaAbstract:Background Drug regulatory agencies (DRA) support prescription of generic products of intravenous antibiotics assuming Therapeutic Equivalence from pharmaceutical Equivalence. Recent reports of deaths associated with generic heparin and metoprolol have raised concerns about the efficacy and safety of DRA-approved drugs. Methodology/Principal Findings To challenge the assumption that pharmaceutical Equivalence predicts Therapeutic Equivalence, we determined in vitro and in vivo the efficacy of the innovator product and 20 pharmaceutically equivalent generics of gentamicin. The data showed that, while only 1 generic product failed in vitro (MIC = 45.3 vs. 0.7 mg/L, P
Mei-ling Chen - One of the best experts on this subject based on the ideXlab platform.
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Harmonization of Regulatory Approaches for Evaluating Therapeutic Equivalence and Interchangeability of Multisource Drug Products: Workshop Summary Report
The AAPS Journal, 2011Co-Authors: Mei-ling Chen, Vinod P. Shah, Daan J. Crommelin, Leon Shargel, Dennis Bashaw, Masood Bhatti, Henning Blume, Jennifer Dressman, Murray Ducharme, Paul FacklerAbstract:Regulatory approaches for evaluating Therapeutic Equivalence of multisource (or generic) drug products vary among different countries and/or regions. Harmonization of these approaches may decrease the number of in vivo bioEquivalence studies and avoid unnecessary drug exposure to humans. Global harmonization for regulatory requirements may be promoted by a better understanding of factors underlying product performance and expectations from different regulatory authorities. This workshop provided an opportunity for pharmaceutical scientists from academia, industry and regulatory agencies to have open discussions on current regulatory issues and industry practices, facilitating harmonization of regulatory approaches for establishing Therapeutic Equivalence and interchangeability of multisource drug products.
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Challenges and Opportunities in Establishing Scientific and Regulatory Standards for Assuring Therapeutic Equivalence of Modified Release Products: Workshop Summary Report
The AAPS journal, 2010Co-Authors: Mei-ling Chen, Vinod P. Shah, Derek A. Ganes, Kamal K. Midha, James Caro, Prabu Nambiar, Mario L. Rocci, Avinash G. Thombre, Bertil Abrahamsson, Dale P. ConnerAbstract:Modified release products are complex dosage forms designed to release drug in a controlled manner to achieve desired efficacy and safety. Inappropriate control of drug release from such products may result in reduced efficacy or increased toxicity. This workshop provided an opportunity for pharmaceutical scientists from academia, industry, and regulatory agencies to discuss current industry practices and regulatory expectations for demonstrating pharmaceutical Equivalence and bioEquivalence of MR products, further facilitating the establishment of regulatory standards for ensuring Therapeutic Equivalence of these products.
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Challenges and opportunities in establishing scientific and regulatory standards for determining Therapeutic Equivalence of modified-release products: Workshop summary report
Clinical therapeutics, 2010Co-Authors: Mei-ling Chen, Vinod P. Shah, Derek A. Ganes, Kamal K. Midha, James Caro, Prabu Nambiar, Mario L. Rocci, Avinash G. Thombre, Bertil Abrahamsson, Dale P. ConnerAbstract:Abstract Background: Modified-release (MR) products are complex dosage forms designed to release drug in a controlled manner to achieve the desired efficacy and safety profiles. Inappropriate control of drug release from such products may result in reduced efficacy or increased toxicity. Objective: This paper is a summary report of the American Association of Pharmaceutical Scientists, International Pharmaceutical Federation, and Product Quality Research Institute workshop titled "Challenges and Opportunities in Establishing Scientific and Regulatory Standards for Assuring Therapeutic Equivalence of Modified Release Products", held October 1–2, 2009, in Baltimore, Maryland. Methods: The workshop provided an opportunity for pharmaceutical scientists from academia, industry, and regulatory agencies to discuss current regulatory expectations and industry practices for evaluating the pharmaceutical Equivalence and bioEquivalence of oral MR products. Results: In the case of conventional monophasic MR formulations, the current regulatory approaches and criteria for bioEquivalence evaluation were considered adequate for the assessment of Therapeutic Equivalence and inter-changeability of drug products. Additional measures may occasionally be needed to determine the bioEquivalence of multiphasic MR products. The metric of partial AUC proposed by the US Food and Drug Administration received broad support as an additional measure for evaluating bioEquivalence of multiphasic MR products designed to have a rapid onset of drug action followed by sustained response. The cutoff for partial AUCs may be based on the pharmacokinetic/pharmacodynamic or pharmacokinetic/ response characteristics of the products under examination. If the new metric is highly variable, the bioEquivalence limits may be set based on the known within-subject vari- ability for the reference product. Conclusions: The current regulatory approaches and criteria for bioEquivalence evaluation were considered adequate for the assessment of Therapeutic Equivalence and interchangeability of conventional monophasic MR products. Additional measures may occasionally be needed to establish the bioEquivalence of multiphasic MR products, and development of such measures is an important objective. The metric of partial AUC was proposed for products designed to have a rapid drug action followed by sustained response.
Dale P. Conner - One of the best experts on this subject based on the ideXlab platform.
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Challenges and Opportunities in Establishing Scientific and Regulatory Standards for Assuring Therapeutic Equivalence of Modified Release Products: Workshop Summary Report
The AAPS journal, 2010Co-Authors: Mei-ling Chen, Vinod P. Shah, Derek A. Ganes, Kamal K. Midha, James Caro, Prabu Nambiar, Mario L. Rocci, Avinash G. Thombre, Bertil Abrahamsson, Dale P. ConnerAbstract:Modified release products are complex dosage forms designed to release drug in a controlled manner to achieve desired efficacy and safety. Inappropriate control of drug release from such products may result in reduced efficacy or increased toxicity. This workshop provided an opportunity for pharmaceutical scientists from academia, industry, and regulatory agencies to discuss current industry practices and regulatory expectations for demonstrating pharmaceutical Equivalence and bioEquivalence of MR products, further facilitating the establishment of regulatory standards for ensuring Therapeutic Equivalence of these products.
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Challenges and opportunities in establishing scientific and regulatory standards for determining Therapeutic Equivalence of modified-release products: Workshop summary report
Clinical therapeutics, 2010Co-Authors: Mei-ling Chen, Vinod P. Shah, Derek A. Ganes, Kamal K. Midha, James Caro, Prabu Nambiar, Mario L. Rocci, Avinash G. Thombre, Bertil Abrahamsson, Dale P. ConnerAbstract:Abstract Background: Modified-release (MR) products are complex dosage forms designed to release drug in a controlled manner to achieve the desired efficacy and safety profiles. Inappropriate control of drug release from such products may result in reduced efficacy or increased toxicity. Objective: This paper is a summary report of the American Association of Pharmaceutical Scientists, International Pharmaceutical Federation, and Product Quality Research Institute workshop titled "Challenges and Opportunities in Establishing Scientific and Regulatory Standards for Assuring Therapeutic Equivalence of Modified Release Products", held October 1–2, 2009, in Baltimore, Maryland. Methods: The workshop provided an opportunity for pharmaceutical scientists from academia, industry, and regulatory agencies to discuss current regulatory expectations and industry practices for evaluating the pharmaceutical Equivalence and bioEquivalence of oral MR products. Results: In the case of conventional monophasic MR formulations, the current regulatory approaches and criteria for bioEquivalence evaluation were considered adequate for the assessment of Therapeutic Equivalence and inter-changeability of drug products. Additional measures may occasionally be needed to determine the bioEquivalence of multiphasic MR products. The metric of partial AUC proposed by the US Food and Drug Administration received broad support as an additional measure for evaluating bioEquivalence of multiphasic MR products designed to have a rapid onset of drug action followed by sustained response. The cutoff for partial AUCs may be based on the pharmacokinetic/pharmacodynamic or pharmacokinetic/ response characteristics of the products under examination. If the new metric is highly variable, the bioEquivalence limits may be set based on the known within-subject vari- ability for the reference product. Conclusions: The current regulatory approaches and criteria for bioEquivalence evaluation were considered adequate for the assessment of Therapeutic Equivalence and interchangeability of conventional monophasic MR products. Additional measures may occasionally be needed to establish the bioEquivalence of multiphasic MR products, and development of such measures is an important objective. The metric of partial AUC was proposed for products designed to have a rapid drug action followed by sustained response.
