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Deepika Aggarwal - One of the best experts on this subject based on the ideXlab platform.
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critical attributes of transdermal drug delivery system tdds a Generic Product development review
Drug Development and Industrial Pharmacy, 2014Co-Authors: P. K. Ruby, Shriram M. Pathak, Deepika AggarwalAbstract:AbstractBioequivalence testing of transdermal drug delivery systems (TDDS) has always been a subject of high concern for Generic companies due to the formulation complexity and the fact that they are subtle to even minor manufacturing differences and hence should be clearly qualified in terms of quality, safety and efficacy. In recent times bioequivalence testing of transdermal patches has gained a global attention and many regulatory authorities worldwide have issued recommendations to set specific framework for demonstrating equivalence between two Products. These current regulatory procedures demand a complete characterization of the Generic formulation in terms of its physicochemical sameness, pharmacokinetics disposition, residual content and/or skin irritation/sensitization testing with respect to the reference formulation. This paper intends to highlight critical in vitro tests in assessing the therapeutic equivalence of Products and also outlines their valuable applications in Generic Product succ...
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establishment of in vitro in vivo equivalence of highly variable drugs a Generic Product development perspective
Pharmaceutical Development and Technology, 2014Co-Authors: Shriram M. Pathak, Deepika AggarwalAbstract:In vivo equivalence of highly variable drugs (HVD) has always been a subject of great concern, in terms of both safety and efficacy, for regulatory agencies. Successful demonstration of their bioequivalence thus presents the most crucial component of a Generic application, significantly contributing toward the cost and time of development. For poorly soluble drugs, such as telmisartan, dissolution represents the rate-limiting step in the gastric region and in many cases may not be complete, thereby contributing to low and highly variable bioavailability. Consequently, simulation of gastrointestinal conditions is essential to adequately predict the in vivo behavior of drug formulations. In this study, we evaluated usefulness of physiologically relevant dissolution method over commonly used acidic media to forecast comparable in vivo performance of telmisartan formulation to that of reference samples. In the present study, telmisartan was classified as a HVD and a partial replicate design with repeating the reference Product and scaling the bioequivalence for the reference variability has been presented. The design has effectively decreased sample size, without increasing patient risk. Results from this project suggest that scaled average bioequivalence (SABE) provides a good approach for evaluating the bioequivalence of HVD, meeting the need for international guidelines for bioequivalence.
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Critical attributes of transdermal drug delivery system (TDDS) – a Generic Product development review
Drug development and industrial pharmacy, 2014Co-Authors: P. K. Ruby, Shriram M. Pathak, Deepika AggarwalAbstract:AbstractBioequivalence testing of transdermal drug delivery systems (TDDS) has always been a subject of high concern for Generic companies due to the formulation complexity and the fact that they are subtle to even minor manufacturing differences and hence should be clearly qualified in terms of quality, safety and efficacy. In recent times bioequivalence testing of transdermal patches has gained a global attention and many regulatory authorities worldwide have issued recommendations to set specific framework for demonstrating equivalence between two Products. These current regulatory procedures demand a complete characterization of the Generic formulation in terms of its physicochemical sameness, pharmacokinetics disposition, residual content and/or skin irritation/sensitization testing with respect to the reference formulation. This paper intends to highlight critical in vitro tests in assessing the therapeutic equivalence of Products and also outlines their valuable applications in Generic Product succ...
P. K. Ruby - One of the best experts on this subject based on the ideXlab platform.
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critical attributes of transdermal drug delivery system tdds a Generic Product development review
Drug Development and Industrial Pharmacy, 2014Co-Authors: P. K. Ruby, Shriram M. Pathak, Deepika AggarwalAbstract:AbstractBioequivalence testing of transdermal drug delivery systems (TDDS) has always been a subject of high concern for Generic companies due to the formulation complexity and the fact that they are subtle to even minor manufacturing differences and hence should be clearly qualified in terms of quality, safety and efficacy. In recent times bioequivalence testing of transdermal patches has gained a global attention and many regulatory authorities worldwide have issued recommendations to set specific framework for demonstrating equivalence between two Products. These current regulatory procedures demand a complete characterization of the Generic formulation in terms of its physicochemical sameness, pharmacokinetics disposition, residual content and/or skin irritation/sensitization testing with respect to the reference formulation. This paper intends to highlight critical in vitro tests in assessing the therapeutic equivalence of Products and also outlines their valuable applications in Generic Product succ...
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Critical attributes of transdermal drug delivery system (TDDS) – a Generic Product development review
Drug development and industrial pharmacy, 2014Co-Authors: P. K. Ruby, Shriram M. Pathak, Deepika AggarwalAbstract:AbstractBioequivalence testing of transdermal drug delivery systems (TDDS) has always been a subject of high concern for Generic companies due to the formulation complexity and the fact that they are subtle to even minor manufacturing differences and hence should be clearly qualified in terms of quality, safety and efficacy. In recent times bioequivalence testing of transdermal patches has gained a global attention and many regulatory authorities worldwide have issued recommendations to set specific framework for demonstrating equivalence between two Products. These current regulatory procedures demand a complete characterization of the Generic formulation in terms of its physicochemical sameness, pharmacokinetics disposition, residual content and/or skin irritation/sensitization testing with respect to the reference formulation. This paper intends to highlight critical in vitro tests in assessing the therapeutic equivalence of Products and also outlines their valuable applications in Generic Product succ...
Omar Vesga - One of the best experts on this subject based on the ideXlab platform.
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Nontherapeutic equivalence of a Generic Product of imipenem-cilastatin is caused more by chemical instability of the active pharmaceutical ingredient (imipenem) than by its substandard amount of cilastatin
2019Co-Authors: Maria Agudelo, Andres F. Zuluaga, Carlos A. Rodriguez, Omar VesgaAbstract:BackgroundWe demonstrated therapeutic nonequivalence of “bioequivalent” Generics for meropenem, but there is no data with Generics of other carbapenems.MethodsOne Generic Product of imipenem-cilastatin was compared with the innovator in terms of in vitro susceptibility testing, pharmaceutical equivalence, pharmacokinetic (PK) and pharmacodynamic (PD) equivalence in the neutropenic mouse thigh, lung and brain infection models. Both pharmaceutical forms were then subjected to analytical chemistry assays (LC/MS).Results and conclusionThe Generic Product had 30% lower concentration of cilastatin compared with the innovator of imipenem-cilastatin. Regarding the active pharmaceutical ingredient (imipenem), we found no differences in MIC, MBC, concentration or potency or AUC, confirming equivalence in terms of in vitro activity. However, the Generic failed therapeutic equivalence in all three animal models. Its Emax against S. aureus in the thigh model was consistently lower, killing from 0.1 to 7.3 million less microorganisms per gram in 24 hours than the innovator (P = 0.003). Against K. pneumoniae in the lung model, the Generic exhibited a conspicuous Eagle effect fitting a Gaussian equation instead of the expected sigmoid curve of the Hill model. In the brain infection model with P. aeruginosa, the Generic failed when bacterial growth was >4 log10 CFU/g in 24 hours, but not if it was less than 2.5 log10 CFU/g. These large differences in the PD profile cannot be explained by the lower concentration of cilastatin, and rather suggested a failure attributable to the imipenem constituent of the Generic Product. Analytical chemistry assays confirmed that, besides having 30% less cilastatin, the Generic imipenem was more acidic, less stable, and exhibited four different degradation masses that were absent in the innovator.
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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
Shriram M. Pathak - One of the best experts on this subject based on the ideXlab platform.
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critical attributes of transdermal drug delivery system tdds a Generic Product development review
Drug Development and Industrial Pharmacy, 2014Co-Authors: P. K. Ruby, Shriram M. Pathak, Deepika AggarwalAbstract:AbstractBioequivalence testing of transdermal drug delivery systems (TDDS) has always been a subject of high concern for Generic companies due to the formulation complexity and the fact that they are subtle to even minor manufacturing differences and hence should be clearly qualified in terms of quality, safety and efficacy. In recent times bioequivalence testing of transdermal patches has gained a global attention and many regulatory authorities worldwide have issued recommendations to set specific framework for demonstrating equivalence between two Products. These current regulatory procedures demand a complete characterization of the Generic formulation in terms of its physicochemical sameness, pharmacokinetics disposition, residual content and/or skin irritation/sensitization testing with respect to the reference formulation. This paper intends to highlight critical in vitro tests in assessing the therapeutic equivalence of Products and also outlines their valuable applications in Generic Product succ...
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establishment of in vitro in vivo equivalence of highly variable drugs a Generic Product development perspective
Pharmaceutical Development and Technology, 2014Co-Authors: Shriram M. Pathak, Deepika AggarwalAbstract:In vivo equivalence of highly variable drugs (HVD) has always been a subject of great concern, in terms of both safety and efficacy, for regulatory agencies. Successful demonstration of their bioequivalence thus presents the most crucial component of a Generic application, significantly contributing toward the cost and time of development. For poorly soluble drugs, such as telmisartan, dissolution represents the rate-limiting step in the gastric region and in many cases may not be complete, thereby contributing to low and highly variable bioavailability. Consequently, simulation of gastrointestinal conditions is essential to adequately predict the in vivo behavior of drug formulations. In this study, we evaluated usefulness of physiologically relevant dissolution method over commonly used acidic media to forecast comparable in vivo performance of telmisartan formulation to that of reference samples. In the present study, telmisartan was classified as a HVD and a partial replicate design with repeating the reference Product and scaling the bioequivalence for the reference variability has been presented. The design has effectively decreased sample size, without increasing patient risk. Results from this project suggest that scaled average bioequivalence (SABE) provides a good approach for evaluating the bioequivalence of HVD, meeting the need for international guidelines for bioequivalence.
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Critical attributes of transdermal drug delivery system (TDDS) – a Generic Product development review
Drug development and industrial pharmacy, 2014Co-Authors: P. K. Ruby, Shriram M. Pathak, Deepika AggarwalAbstract:AbstractBioequivalence testing of transdermal drug delivery systems (TDDS) has always been a subject of high concern for Generic companies due to the formulation complexity and the fact that they are subtle to even minor manufacturing differences and hence should be clearly qualified in terms of quality, safety and efficacy. In recent times bioequivalence testing of transdermal patches has gained a global attention and many regulatory authorities worldwide have issued recommendations to set specific framework for demonstrating equivalence between two Products. These current regulatory procedures demand a complete characterization of the Generic formulation in terms of its physicochemical sameness, pharmacokinetics disposition, residual content and/or skin irritation/sensitization testing with respect to the reference formulation. This paper intends to highlight critical in vitro tests in assessing the therapeutic equivalence of Products and also outlines their valuable applications in Generic Product succ...
Maria Agudelo - One of the best experts on this subject based on the ideXlab platform.
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Nontherapeutic equivalence of a Generic Product of imipenem-cilastatin is caused more by chemical instability of the active pharmaceutical ingredient (imipenem) than by its substandard amount of cilastatin
2019Co-Authors: Maria Agudelo, Andres F. Zuluaga, Carlos A. Rodriguez, Omar VesgaAbstract:BackgroundWe demonstrated therapeutic nonequivalence of “bioequivalent” Generics for meropenem, but there is no data with Generics of other carbapenems.MethodsOne Generic Product of imipenem-cilastatin was compared with the innovator in terms of in vitro susceptibility testing, pharmaceutical equivalence, pharmacokinetic (PK) and pharmacodynamic (PD) equivalence in the neutropenic mouse thigh, lung and brain infection models. Both pharmaceutical forms were then subjected to analytical chemistry assays (LC/MS).Results and conclusionThe Generic Product had 30% lower concentration of cilastatin compared with the innovator of imipenem-cilastatin. Regarding the active pharmaceutical ingredient (imipenem), we found no differences in MIC, MBC, concentration or potency or AUC, confirming equivalence in terms of in vitro activity. However, the Generic failed therapeutic equivalence in all three animal models. Its Emax against S. aureus in the thigh model was consistently lower, killing from 0.1 to 7.3 million less microorganisms per gram in 24 hours than the innovator (P = 0.003). Against K. pneumoniae in the lung model, the Generic exhibited a conspicuous Eagle effect fitting a Gaussian equation instead of the expected sigmoid curve of the Hill model. In the brain infection model with P. aeruginosa, the Generic failed when bacterial growth was >4 log10 CFU/g in 24 hours, but not if it was less than 2.5 log10 CFU/g. These large differences in the PD profile cannot be explained by the lower concentration of cilastatin, and rather suggested a failure attributable to the imipenem constituent of the Generic Product. Analytical chemistry assays confirmed that, besides having 30% less cilastatin, the Generic imipenem was more acidic, less stable, and exhibited four different degradation masses that were absent in the innovator.
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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