In vivo bioequivalence studies to prove drug interchangeability
Keywords:
THERAPEUTIC EQUIVALENCE, INTERCHANGE OF DRUGS
Abstract
Introduction: the demand to prove the interchangeability of generic drugs with innovative medicines originated in 1970, in the developed world.
Objective: the present article comprises a brief historical summary, pointing out the first drugs that caused bioequivalence problems.
Results: the study states the implementation of interchangeability in Latin America started the first decade of the current century, encouraged by a working team of the PAHO, and in January, 2007, Uruguay passed the first laws on this matter.
The concepts of drug bioequivalence and interchangeability are defined and the drugs that should observe this regulation are mentioned. The criteria for the design of a priorities list for the demand of bioequivalence are examined, and a review of the regulatory framework in our country since 2007 is also included in the present study.
Reference to specific designs of these studies is made, aiming to assess the interaction of the new retard formulations with food or to minimize the effects of intra-individual variability on the statistical value of the studies.
Conclusions: a few improvable details in terms of regulation and the impact of bioequivalence studies on prescription habits, the pharmaceutical market in Uruguay and accessibility to effective and safe drugs are commented upon.
References
(1) Jounela AJ, Sothmann A. Bioavailability of Digoxin. Lancet 1973; 1(7796):202-3.
(2) Albert KS, Sakmar E, Hallmark MR, Weidler DJ, Wagner JG. Bioavailability of diphenylhydantoin. Clin Pharmacol Ther 1974; 16(4):727-35.
(3) Soryal I, Richens A. Bioavailability and dissolution of proprietary and generic formulations of Phenytoin. J Neurol Neurosurg Psychiatry 1992; 55(8):688-91.
(4) Bennett WM, DeMattos A, Norman DJ, Meyer MM, Olyaei A. Which Cyclosporin formulation? Lancet 1996; 348(9021):205.
(5) Vercaigne LM, Zhanel GG. Clinical significance of bioequivalence and interchangeability of narrow therapeutics range drugs: focus on warfarins. J Pharm Pharm Sci 1998; 1(3):92-4.
(6) Ross MB. Status of generic substitution: problematic drug classes reviewed. Hosp Formul 1989; 24(8):441-4, 447-9.
(7) Organización Panamericana de la Salud. Criterios científicos para los ensayos de bioequivalencia (in vivo e in vitro), las bioexenciones y las estrategias para su implementación: documento borrador. En: IV Conferencia Paneamericana para la Armonización de la Reglamentación Farmacéutica. Republica Dominicana 2-4 de Marzo , 2005. p.6. Disponible en: http://www.paho.org/spanish/ad/ths/ev/bedocumentocientificoborradorespanol.pdf Consulta: 11 julio 2012.
(8) World Health Organization. Additional guidance for organizations performing in vivo bioequivalence studies. In: Fortieth report of the WHO Expert Committee on Specifications for Pharmaceutical Preparations: Annex 9. Technical Report Series, No. 937. Geneva: WHO, 2006.
(9) European Medicines Agency. ICH Topic E 6 (R1):guideline for good clinical practice. Disponible en: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002874.pdf Consulta: 6 julio 2012.
(10) Hauschke D, Steinijans V, Pigeot I. Bioquivalence studies in drug development: methods and applications. West Sussex, England: Wiley, 2007.
(11) Schulz HU, Steinijans VW. Striving for standards in bioquivalence Assessment: a review. Int J Clin Pharmacol Ther Toxicol 1992; 30 (Suppl. 1):S1-6.
(12) United States. Department of Health and Human Services. Food and Drug Administration. Center for Drug Evaluation and Research. Guidance for industry: bioavailability and bioequivalence studies for orally administered drug products. General considerations. Washington, DC: CDER, 2003. Disponible en: http://www.fda.gov/downloads/ Drugs/.../Guidances/ucm070124.pdf. Consulta: 11 julio 2012.
(13) European Medicines Agency. Note for guidance on the investigation of bioavailability and bioequivalence. London: EMA, 2001. Disponible en: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003008.pdf Consulta: 11 julio 2012.
(14) Estévez Carrizo FE. Estudios de bioequivalencia: enfoque metodológico y aplicaciones prácticas en la evaluación de medicamentos genéricos. Rev Med Urug 2000; 16(2):133-43.
(15) Decreto N° 12/2007. Recomendaciones técnicas para la realización de estudios de bioquivalencia. Montevideo, Uruguay 12 de enero de 2007. Disponible en: http://archivo.presidencia.gub.uy/_Web/decretos/2007/01/266_15%2009%202006_00001.PDF Consulta: 11 julio 2012.
(16) United States Department of Health and Human Services. Food and Drug Administration. Center for Drug Evaluation Research. Guidance for industry: Food effect on bioavailability and fed bioequivalence studies. Washington DC: 2002. Diponible en : http://www.fda.gov/downloads/regulatoryinformation/guidances/ucm126833.pdf Consulta:11 julio 2012)
(17) Disposición 1746/2007 - ANMAT. Sustitúyese el Anexo I de la disposición 5040/2006, referido al Régimen de Buenas Prácticas para la Realización de Estudios de Biodisponibilidad/Bioequivalencia. Buenos Aires, Argentina 2007.
(18) Decreto Nro. 379/008. Investigación en seres humanos: aspectos éticos de la investigación que involucra seres humanos. Montevideo, Uruguay 4 de Agosto de 2008. Disponible en: http://archivo.presidencia.gub.uy/_web/decretos/2008/ 08/CM515_26%2006%202008_00001.PDF Consulta: 11 julio 2012.
(19) Decreto N° 261/009. Reglamentación de los centros y de los estudios de biodisponibilidad comparativa y/o bioequivalenica "in vivo" de medicamentos. Montevideo, Uruguay 1 de Junio de 2009. Disponible en: http://archivo.presidencia.gub.uy/_web/decretos/2009/06/ASUNTO74.pdf Consulta: 11 julio 2012.
(20) Decreto N° 369/010. Referencias para la realización de estudios de biodisponibilidad y bioequivalencia de medicamentos. Montevideo, Uruguay 13 de diciembre de 2010. Disponible en: http://archivo.presidencia.gub.uy/sci/decretos/2010/ 12/msp_97.pdf Consulta: 11 julio 2011.
(21) Decreto N° 097/011. Recomendaciones técnicas para la realización de estudios de equivalencia biofarmacéutica en centros especializados debidamente habilitados. Montevideo, Uruguay 2 de marzo de 2011. Disponible en: http://archivo.presidencia.gub.uy/sci/decretos/2011/03/msp_197.pdf Consulta: 11 julio 2012.
(22) Parrillo-Campiglia S, Cedrés M, Umpierrez O, Rodríguez P, Márquez S, Guarneri C, et al. Bioequivalence of two film-coated tablets of imatinib mesylate 400 mg: a randomized, open-label, single-dose, fasting, two-period, two-sequence crossover comparison in healthy male South American volunteers. Clin Ther 2009; 31(10):2224-32.
(23) Estévez Carrizo FE, Parrillo S, Cedres M, Estévez Parrillo FT, Rodríguez P. Comparative bioavailability of two oral formulations of mycophenolate mofetil in healthy adult Uruguayan subjects: a case of highly variable rate of drug absorption. Int J Clin Pharmacol Ther 2010; 48(9):621-7.
(24) Estévez Carrizo FE, Parrillo S, Cedrés M, Estévez Parrillo FT. Single dose relative bioavailability of a new quetiapine fumarate extended release formulation: a postprandial, randomized, open- label, two-way, crossover study in healthy Uruguayan volunteers. Clin Ther 2011; 33(6):738-45.
(25) Estévez Carrizo FE, Ruíz S, Bellocq B, Leal C, Siri MT, del Campo MJ. Simultaneous itraconazole bioequivalence assessment and CYP3A phenotyping in Southamerican subjects. Int J Clin Pharmacol Ther 2005; 43(2):109-16.
(26) Endrenyi L, Fritsch S, Yan W. Cmax/AUC is a clearer measure than Cmax for absorption rates in investigation of bioequivalence. Int J Clin Pharmacol Ther Toxicol 1991; 29(10):394-9.
(27) Lacey LF, Keene ON, Duquesnoy C, Bye A. Evaluation of different indirect measures of rate of drug absorption in comparative pharmacokinetic studies. J Pharm Sci 1994; 83(2):212-15.
(28) Schall R, Luus HG, Steinijans VW, Hauschke D. Choice of characteristics and their bioequivalence ranges for the comparison of absorption rates of immediate-release drug formulations. Int J Clin Pharmacol Ther 1994; 32(7):323-8.
(29) Estévez Carrizo F, Giusti M, Parrillo S. Dextromethorphan O-demethylation genetic polymorphism in a hybrid South American population. Clin Pharmacol Ther 1999; 65(2):166.
(30) Estevez F, Giusti M, Parrillo S, Oxandabarat J. Dextromethorphan O-demethylation polymorphism in the Uruguayan population. Eur J Clin Pharmacol 1997; 52(5):417-8.
(2) Albert KS, Sakmar E, Hallmark MR, Weidler DJ, Wagner JG. Bioavailability of diphenylhydantoin. Clin Pharmacol Ther 1974; 16(4):727-35.
(3) Soryal I, Richens A. Bioavailability and dissolution of proprietary and generic formulations of Phenytoin. J Neurol Neurosurg Psychiatry 1992; 55(8):688-91.
(4) Bennett WM, DeMattos A, Norman DJ, Meyer MM, Olyaei A. Which Cyclosporin formulation? Lancet 1996; 348(9021):205.
(5) Vercaigne LM, Zhanel GG. Clinical significance of bioequivalence and interchangeability of narrow therapeutics range drugs: focus on warfarins. J Pharm Pharm Sci 1998; 1(3):92-4.
(6) Ross MB. Status of generic substitution: problematic drug classes reviewed. Hosp Formul 1989; 24(8):441-4, 447-9.
(7) Organización Panamericana de la Salud. Criterios científicos para los ensayos de bioequivalencia (in vivo e in vitro), las bioexenciones y las estrategias para su implementación: documento borrador. En: IV Conferencia Paneamericana para la Armonización de la Reglamentación Farmacéutica. Republica Dominicana 2-4 de Marzo , 2005. p.6. Disponible en: http://www.paho.org/spanish/ad/ths/ev/bedocumentocientificoborradorespanol.pdf Consulta: 11 julio 2012.
(8) World Health Organization. Additional guidance for organizations performing in vivo bioequivalence studies. In: Fortieth report of the WHO Expert Committee on Specifications for Pharmaceutical Preparations: Annex 9. Technical Report Series, No. 937. Geneva: WHO, 2006.
(9) European Medicines Agency. ICH Topic E 6 (R1):guideline for good clinical practice. Disponible en: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002874.pdf Consulta: 6 julio 2012.
(10) Hauschke D, Steinijans V, Pigeot I. Bioquivalence studies in drug development: methods and applications. West Sussex, England: Wiley, 2007.
(11) Schulz HU, Steinijans VW. Striving for standards in bioquivalence Assessment: a review. Int J Clin Pharmacol Ther Toxicol 1992; 30 (Suppl. 1):S1-6.
(12) United States. Department of Health and Human Services. Food and Drug Administration. Center for Drug Evaluation and Research. Guidance for industry: bioavailability and bioequivalence studies for orally administered drug products. General considerations. Washington, DC: CDER, 2003. Disponible en: http://www.fda.gov/downloads/ Drugs/.../Guidances/ucm070124.pdf. Consulta: 11 julio 2012.
(13) European Medicines Agency. Note for guidance on the investigation of bioavailability and bioequivalence. London: EMA, 2001. Disponible en: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003008.pdf Consulta: 11 julio 2012.
(14) Estévez Carrizo FE. Estudios de bioequivalencia: enfoque metodológico y aplicaciones prácticas en la evaluación de medicamentos genéricos. Rev Med Urug 2000; 16(2):133-43.
(15) Decreto N° 12/2007. Recomendaciones técnicas para la realización de estudios de bioquivalencia. Montevideo, Uruguay 12 de enero de 2007. Disponible en: http://archivo.presidencia.gub.uy/_Web/decretos/2007/01/266_15%2009%202006_00001.PDF Consulta: 11 julio 2012.
(16) United States Department of Health and Human Services. Food and Drug Administration. Center for Drug Evaluation Research. Guidance for industry: Food effect on bioavailability and fed bioequivalence studies. Washington DC: 2002. Diponible en : http://www.fda.gov/downloads/regulatoryinformation/guidances/ucm126833.pdf Consulta:11 julio 2012)
(17) Disposición 1746/2007 - ANMAT. Sustitúyese el Anexo I de la disposición 5040/2006, referido al Régimen de Buenas Prácticas para la Realización de Estudios de Biodisponibilidad/Bioequivalencia. Buenos Aires, Argentina 2007.
(18) Decreto Nro. 379/008. Investigación en seres humanos: aspectos éticos de la investigación que involucra seres humanos. Montevideo, Uruguay 4 de Agosto de 2008. Disponible en: http://archivo.presidencia.gub.uy/_web/decretos/2008/ 08/CM515_26%2006%202008_00001.PDF Consulta: 11 julio 2012.
(19) Decreto N° 261/009. Reglamentación de los centros y de los estudios de biodisponibilidad comparativa y/o bioequivalenica "in vivo" de medicamentos. Montevideo, Uruguay 1 de Junio de 2009. Disponible en: http://archivo.presidencia.gub.uy/_web/decretos/2009/06/ASUNTO74.pdf Consulta: 11 julio 2012.
(20) Decreto N° 369/010. Referencias para la realización de estudios de biodisponibilidad y bioequivalencia de medicamentos. Montevideo, Uruguay 13 de diciembre de 2010. Disponible en: http://archivo.presidencia.gub.uy/sci/decretos/2010/ 12/msp_97.pdf Consulta: 11 julio 2011.
(21) Decreto N° 097/011. Recomendaciones técnicas para la realización de estudios de equivalencia biofarmacéutica en centros especializados debidamente habilitados. Montevideo, Uruguay 2 de marzo de 2011. Disponible en: http://archivo.presidencia.gub.uy/sci/decretos/2011/03/msp_197.pdf Consulta: 11 julio 2012.
(22) Parrillo-Campiglia S, Cedrés M, Umpierrez O, Rodríguez P, Márquez S, Guarneri C, et al. Bioequivalence of two film-coated tablets of imatinib mesylate 400 mg: a randomized, open-label, single-dose, fasting, two-period, two-sequence crossover comparison in healthy male South American volunteers. Clin Ther 2009; 31(10):2224-32.
(23) Estévez Carrizo FE, Parrillo S, Cedres M, Estévez Parrillo FT, Rodríguez P. Comparative bioavailability of two oral formulations of mycophenolate mofetil in healthy adult Uruguayan subjects: a case of highly variable rate of drug absorption. Int J Clin Pharmacol Ther 2010; 48(9):621-7.
(24) Estévez Carrizo FE, Parrillo S, Cedrés M, Estévez Parrillo FT. Single dose relative bioavailability of a new quetiapine fumarate extended release formulation: a postprandial, randomized, open- label, two-way, crossover study in healthy Uruguayan volunteers. Clin Ther 2011; 33(6):738-45.
(25) Estévez Carrizo FE, Ruíz S, Bellocq B, Leal C, Siri MT, del Campo MJ. Simultaneous itraconazole bioequivalence assessment and CYP3A phenotyping in Southamerican subjects. Int J Clin Pharmacol Ther 2005; 43(2):109-16.
(26) Endrenyi L, Fritsch S, Yan W. Cmax/AUC is a clearer measure than Cmax for absorption rates in investigation of bioequivalence. Int J Clin Pharmacol Ther Toxicol 1991; 29(10):394-9.
(27) Lacey LF, Keene ON, Duquesnoy C, Bye A. Evaluation of different indirect measures of rate of drug absorption in comparative pharmacokinetic studies. J Pharm Sci 1994; 83(2):212-15.
(28) Schall R, Luus HG, Steinijans VW, Hauschke D. Choice of characteristics and their bioequivalence ranges for the comparison of absorption rates of immediate-release drug formulations. Int J Clin Pharmacol Ther 1994; 32(7):323-8.
(29) Estévez Carrizo F, Giusti M, Parrillo S. Dextromethorphan O-demethylation genetic polymorphism in a hybrid South American population. Clin Pharmacol Ther 1999; 65(2):166.
(30) Estevez F, Giusti M, Parrillo S, Oxandabarat J. Dextromethorphan O-demethylation polymorphism in the Uruguayan population. Eur J Clin Pharmacol 1997; 52(5):417-8.
Published
2012-09-30
How to Cite
1.
Estévez F, Parrillo S, Cedrés M. In vivo bioequivalence studies to prove drug interchangeability. Rev. Méd. Urug. [Internet]. 2012Sep.30 [cited 2024May18];28(3):165-73. Available from: http://www2.rmu.org.uy/ojsrmu311/index.php/rmu/article/view/335
Section
Original Articles
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
