Determination of Therapeutic Equivalence (TE) of 5 Generic Products (GP) of Penicillin G (PEN) Using the Neutropenic Murine Thigh Infection Model (NMTIM)

ABSTRACT: Background: Legal use of GP in human and veterinary medicine has great impact in price regulation worldwide, but numbers of GP makers are increasing overwhelmingly. Beyond quality problems, concern is growing about the scientific basis of using bioequivalence (BE) as surrogate proof of TE,...

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Autores:
Zuluaga Salazar, Andrés Felipe
Agudelo Pérez, María
Salazar Giraldo, Beatriz
Rodríguez Jaramillo, Carlos Andrés
Vesga Meneses, Omar
Tipo de recurso:
Article of investigation
Fecha de publicación:
2004
Institución:
Universidad de Antioquia
Repositorio:
Repositorio UdeA
Idioma:
eng
OAI Identifier:
oai:bibliotecadigital.udea.edu.co:10495/26412
Acceso en línea:
http://hdl.handle.net/10495/26412
Palabra clave:
Penicilina G
Penicillin G
Medicamentos Genéricos
Drugs, Generic
Equivalencia Terapéutica
Therapeutic Equivalency
Rights
openAccess
License
http://purl.org/coar/access_right/c_abf2
id UDEA2_73a0bf643f4fb1605470adeaa402c50b
oai_identifier_str oai:bibliotecadigital.udea.edu.co:10495/26412
network_acronym_str UDEA2
network_name_str Repositorio UdeA
repository_id_str
dc.title.spa.fl_str_mv Determination of Therapeutic Equivalence (TE) of 5 Generic Products (GP) of Penicillin G (PEN) Using the Neutropenic Murine Thigh Infection Model (NMTIM)
title Determination of Therapeutic Equivalence (TE) of 5 Generic Products (GP) of Penicillin G (PEN) Using the Neutropenic Murine Thigh Infection Model (NMTIM)
spellingShingle Determination of Therapeutic Equivalence (TE) of 5 Generic Products (GP) of Penicillin G (PEN) Using the Neutropenic Murine Thigh Infection Model (NMTIM)
Penicilina G
Penicillin G
Medicamentos Genéricos
Drugs, Generic
Equivalencia Terapéutica
Therapeutic Equivalency
title_short Determination of Therapeutic Equivalence (TE) of 5 Generic Products (GP) of Penicillin G (PEN) Using the Neutropenic Murine Thigh Infection Model (NMTIM)
title_full Determination of Therapeutic Equivalence (TE) of 5 Generic Products (GP) of Penicillin G (PEN) Using the Neutropenic Murine Thigh Infection Model (NMTIM)
title_fullStr Determination of Therapeutic Equivalence (TE) of 5 Generic Products (GP) of Penicillin G (PEN) Using the Neutropenic Murine Thigh Infection Model (NMTIM)
title_full_unstemmed Determination of Therapeutic Equivalence (TE) of 5 Generic Products (GP) of Penicillin G (PEN) Using the Neutropenic Murine Thigh Infection Model (NMTIM)
title_sort Determination of Therapeutic Equivalence (TE) of 5 Generic Products (GP) of Penicillin G (PEN) Using the Neutropenic Murine Thigh Infection Model (NMTIM)
dc.creator.fl_str_mv Zuluaga Salazar, Andrés Felipe
Agudelo Pérez, María
Salazar Giraldo, Beatriz
Rodríguez Jaramillo, Carlos Andrés
Vesga Meneses, Omar
dc.contributor.author.none.fl_str_mv Zuluaga Salazar, Andrés Felipe
Agudelo Pérez, María
Salazar Giraldo, Beatriz
Rodríguez Jaramillo, Carlos Andrés
Vesga Meneses, Omar
dc.subject.decs.none.fl_str_mv Penicilina G
Penicillin G
Medicamentos Genéricos
Drugs, Generic
Equivalencia Terapéutica
Therapeutic Equivalency
topic Penicilina G
Penicillin G
Medicamentos Genéricos
Drugs, Generic
Equivalencia Terapéutica
Therapeutic Equivalency
description ABSTRACT: Background: Legal use of GP in human and veterinary medicine has great impact in price regulation worldwide, but numbers of GP makers are increasing overwhelmingly. Beyond quality problems, concern is growing about the scientific basis of using bioequivalence (BE) as surrogate proof of TE, the accepted dogma. To test it, bactericidal efficacy of GP of PEN made in Colombia was compared in vitro and in vivo against the original compound (OC) in simultaneous experiments, employing the same methods required for new antimicrobials. Methods: Microbiologic assays with S. aureus ATCC 6538p and broth microdilution minimal inhibitory and bactericidal concentrations (MIC/MBC) were used to determine BE by comparison of standard curves (SC) and in vitro activity. The NMTIM used 6 week-old specific pathogen free ICR:CD-1 female mice weighting 25±2 g infected with S. aureus GRP-0057, a PEN-susceptible clinical isolante. The sigmoid dose-response model was applied to calculate by least squares nonlinear regression (NLR) pharmacodynamic parameters (PDP) like Emax and bacteriostatic dose (BD). SC were compared by linear curve fitting analysis (CFA), whole NLR by nonlinear CFA, individual PDP by nonlinear CFA and Wilcoxon-Mann-Whitney test (WMW), MIC/MBC by WMW. Results: All 5 GP were made in Colombia; 1 had greater amounts of PEN (intercept = 0.0052 vs 0.0041 mg/l, P<0.0001), but did not differ in MIC/MBC from the OC. Only 1 of the other 4 GP had lower MIC/MBC, 0.01/0.02 vs 0.07/0.10 mg/l for the OC (P = 0.013). Mice had 104.49-4.74 CFU/thigh (CFU/g) when treated with PEN 0.094-24 mg/kg for 24 hours (24h) divided q1h. At the end of therapy, untreated controls had 107.65-7.83 CFU/g (24h growth = 2.92-3.33 log10 CFU/g). All 5 GP failed TE: Emax = 2.01-3.26 vs 4.87 log10 CFU/g, and BD = 6.94-120.1 vs 1.65 mg/kg/24h for GP and OC respectively (P<0.0005). Conclusions: GP of PEN do not exhibit TE with the OC. Current criteria for BE and TE deserve review.
publishDate 2004
dc.date.issued.none.fl_str_mv 2004
dc.date.accessioned.none.fl_str_mv 2022-03-04T23:05:19Z
dc.date.available.none.fl_str_mv 2022-03-04T23:05:19Z
dc.type.spa.fl_str_mv info:eu-repo/semantics/article
dc.type.coarversion.fl_str_mv http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.hasversion.spa.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.coar.spa.fl_str_mv http://purl.org/coar/resource_type/c_2df8fbb1
dc.type.redcol.spa.fl_str_mv https://purl.org/redcol/resource_type/ART
dc.type.local.spa.fl_str_mv Artículo de investigación
format http://purl.org/coar/resource_type/c_2df8fbb1
status_str publishedVersion
dc.identifier.issn.none.fl_str_mv 0733-6373
dc.identifier.uri.none.fl_str_mv http://hdl.handle.net/10495/26412
identifier_str_mv 0733-6373
url http://hdl.handle.net/10495/26412
dc.language.iso.spa.fl_str_mv eng
language eng
dc.rights.spa.fl_str_mv info:eu-repo/semantics/openAccess
dc.rights.accessrights.spa.fl_str_mv http://purl.org/coar/access_right/c_abf2
dc.rights.creativecommons.spa.fl_str_mv Derechos reservados - Está prohibida la reproducción parcial o total de esta publicación
eu_rights_str_mv openAccess
rights_invalid_str_mv http://purl.org/coar/access_right/c_abf2
Derechos reservados - Está prohibida la reproducción parcial o total de esta publicación
dc.format.extent.spa.fl_str_mv 1
dc.format.mimetype.spa.fl_str_mv application/pdf
dc.publisher.spa.fl_str_mv American Society for Microbiology
dc.publisher.group.spa.fl_str_mv GRIPE: Grupo Investigador de Problemas en Enfermedades Infecciosas
dc.publisher.place.spa.fl_str_mv Washington, Estados Unidos
institution Universidad de Antioquia
bitstream.url.fl_str_mv http://bibliotecadigital.udea.edu.co/bitstream/10495/26412/3/AndresZuluaga_2004_DeterminationPenicillinNneutropenic.pdf
http://bibliotecadigital.udea.edu.co/bitstream/10495/26412/2/license.txt
bitstream.checksum.fl_str_mv a4c986a6121fd0aeec48eb2b3ad7d1ec
8a4605be74aa9ea9d79846c1fba20a33
bitstream.checksumAlgorithm.fl_str_mv MD5
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repository.name.fl_str_mv Repositorio Institucional Universidad de Antioquia
repository.mail.fl_str_mv andres.perez@udea.edu.co
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spelling Zuluaga Salazar, Andrés FelipeAgudelo Pérez, MaríaSalazar Giraldo, BeatrizRodríguez Jaramillo, Carlos AndrésVesga Meneses, Omar2022-03-04T23:05:19Z2022-03-04T23:05:19Z20040733-6373http://hdl.handle.net/10495/26412ABSTRACT: Background: Legal use of GP in human and veterinary medicine has great impact in price regulation worldwide, but numbers of GP makers are increasing overwhelmingly. Beyond quality problems, concern is growing about the scientific basis of using bioequivalence (BE) as surrogate proof of TE, the accepted dogma. To test it, bactericidal efficacy of GP of PEN made in Colombia was compared in vitro and in vivo against the original compound (OC) in simultaneous experiments, employing the same methods required for new antimicrobials. Methods: Microbiologic assays with S. aureus ATCC 6538p and broth microdilution minimal inhibitory and bactericidal concentrations (MIC/MBC) were used to determine BE by comparison of standard curves (SC) and in vitro activity. The NMTIM used 6 week-old specific pathogen free ICR:CD-1 female mice weighting 25±2 g infected with S. aureus GRP-0057, a PEN-susceptible clinical isolante. The sigmoid dose-response model was applied to calculate by least squares nonlinear regression (NLR) pharmacodynamic parameters (PDP) like Emax and bacteriostatic dose (BD). SC were compared by linear curve fitting analysis (CFA), whole NLR by nonlinear CFA, individual PDP by nonlinear CFA and Wilcoxon-Mann-Whitney test (WMW), MIC/MBC by WMW. Results: All 5 GP were made in Colombia; 1 had greater amounts of PEN (intercept = 0.0052 vs 0.0041 mg/l, P<0.0001), but did not differ in MIC/MBC from the OC. Only 1 of the other 4 GP had lower MIC/MBC, 0.01/0.02 vs 0.07/0.10 mg/l for the OC (P = 0.013). Mice had 104.49-4.74 CFU/thigh (CFU/g) when treated with PEN 0.094-24 mg/kg for 24 hours (24h) divided q1h. At the end of therapy, untreated controls had 107.65-7.83 CFU/g (24h growth = 2.92-3.33 log10 CFU/g). All 5 GP failed TE: Emax = 2.01-3.26 vs 4.87 log10 CFU/g, and BD = 6.94-120.1 vs 1.65 mg/kg/24h for GP and OC respectively (P<0.0005). Conclusions: GP of PEN do not exhibit TE with the OC. Current criteria for BE and TE deserve review.COL00057441application/pdfengAmerican Society for MicrobiologyGRIPE: Grupo Investigador de Problemas en Enfermedades InfecciosasWashington, Estados Unidosinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_2df8fbb1https://purl.org/redcol/resource_type/ARTArtículo de investigaciónhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2Derechos reservados - Está prohibida la reproducción parcial o total de esta publicaciónDetermination of Therapeutic Equivalence (TE) of 5 Generic Products (GP) of Penicillin G (PEN) Using the Neutropenic Murine Thigh Infection Model (NMTIM)Penicilina GPenicillin GMedicamentos GenéricosDrugs, GenericEquivalencia TerapéuticaTherapeutic EquivalencyAbstracts of the Interscience Conference on Antimicrobial Agents and Chemotherapy4040ORIGINALAndresZuluaga_2004_DeterminationPenicillinNneutropenic.pdfAndresZuluaga_2004_DeterminationPenicillinNneutropenic.pdfArtículo de investigaciónapplication/pdf7435432http://bibliotecadigital.udea.edu.co/bitstream/10495/26412/3/AndresZuluaga_2004_DeterminationPenicillinNneutropenic.pdfa4c986a6121fd0aeec48eb2b3ad7d1ecMD53LICENSElicense.txtlicense.txttext/plain; charset=utf-81748http://bibliotecadigital.udea.edu.co/bitstream/10495/26412/2/license.txt8a4605be74aa9ea9d79846c1fba20a33MD5210495/26412oai:bibliotecadigital.udea.edu.co:10495/264122022-03-04 18:07:03.035Repositorio Institucional Universidad de Antioquiaandres.perez@udea.edu.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