Esperanza González-Rojano1, Julio Marcotegui2, Susana Morales-Alcelay3, Covadonga Álvarez4, John Gordon5, Francisco Abad-Santos1, Alfredo García-Arieta6. 1. Clinical Pharmacology Service, Hospital Universitario de La Princesa, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria la Princesa (IIS-IP), Universidad Autónoma de Madrid (UAM), Madrid, Spain. 2. Department of Anaesthesiology, Reanimation and Pain Treatment, Hospital Clínico San Carlos, Madrid, Spain. 3. Service on Pharmacokinetics and Generics, Division of Pharmacology and Clinical Evaluation, Department of Human Use Medicines, Spanish Agency for Medicines and Health Care Products (AEMPS), C/ Campezo 1, Edificio 8, Planta 2 A, 28022, Madrid, Spain. 4. Pharmaceutical Technology, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain. 5. Division of Biopharmaceutics Evaluation, Bureau of Pharmaceutical Sciences, Therapeutic Products Directorate, Health Canada, Ottawa, Canada. 6. Service on Pharmacokinetics and Generics, Division of Pharmacology and Clinical Evaluation, Department of Human Use Medicines, Spanish Agency for Medicines and Health Care Products (AEMPS), C/ Campezo 1, Edificio 8, Planta 2 A, 28022, Madrid, Spain. agarciaa@aemps.es.
Abstract
PURPOSE: The existence of a sex-by-formulation interaction in bioequivalence studies implies that the bioequivalence results (i.e., the test/reference ratio of the pharmacokinetic parameters) obtained in one sex are not similar to those obtained in the other sex. Therefore, results obtained in studies including only males may not be representative of the results obtained in females and vice versa. The best evidence of the existence of a sex-by-formulation interaction has been obtained from a study conducted with transdermal patches. This observation might be caused by the different characteristics of the skin of males and females. The purpose of this work is to investigate the existence of a sex-by-formulation interaction in all bioequivalence studies of transdermal patches submitted to the Spanish Agency for Medicines between 2010 and 2016. METHODS: Only five different products (Buprenorphine-1, Fentantyl-1, Fentanyl-2, Rivastigmine-1 and Rivastigmine-2) that were submitted for registration included nine bioequivalence studies conducted in males and females. As single dose and multiple dose studies are required for registration of transdermal patches in the European Union, more than one study may be available to confirm the existence of a sex-by-formulation interaction. RESULTS: A sex-by-formulation interaction is suggested in six out of 27 datasets (22%), corresponding to two products, and it is statistically significant in three of them (11%). CONCLUSIONS: The sex-by-formulation interaction detected in some pharmacokinetic parameters of some studies is excluded when the study is repeated, which shows that these results are not reproducible. There is no evidence to require bioequivalence demonstration for transdermal patches in males and females separately.
PURPOSE: The existence of a sex-by-formulation interaction in bioequivalence studies implies that the bioequivalence results (i.e., the test/reference ratio of the pharmacokinetic parameters) obtained in one sex are not similar to those obtained in the other sex. Therefore, results obtained in studies including only males may not be representative of the results obtained in females and vice versa. The best evidence of the existence of a sex-by-formulation interaction has been obtained from a study conducted with transdermal patches. This observation might be caused by the different characteristics of the skin of males and females. The purpose of this work is to investigate the existence of a sex-by-formulation interaction in all bioequivalence studies of transdermal patches submitted to the Spanish Agency for Medicines between 2010 and 2016. METHODS: Only five different products (Buprenorphine-1, Fentantyl-1, Fentanyl-2, Rivastigmine-1 and Rivastigmine-2) that were submitted for registration included nine bioequivalence studies conducted in males and females. As single dose and multiple dose studies are required for registration of transdermal patches in the European Union, more than one study may be available to confirm the existence of a sex-by-formulation interaction. RESULTS: A sex-by-formulation interaction is suggested in six out of 27 datasets (22%), corresponding to two products, and it is statistically significant in three of them (11%). CONCLUSIONS: The sex-by-formulation interaction detected in some pharmacokinetic parameters of some studies is excluded when the study is repeated, which shows that these results are not reproducible. There is no evidence to require bioequivalence demonstration for transdermal patches in males and females separately.
Authors: Alfredo García-Arieta; Susana Morales-Alcelay; Marta Herranz; José María de la Torre-Alvarado; Antonio Blázquez-Pérez; Ma Luisa Suárez-Gea; Covadonga Alvarez Journal: Int J Pharm Date: 2011-11-20 Impact factor: 5.875