title: Investigation on the need of multiple dose bioequivalence studies for prolonged-release generic products.
abstract: In the European Union multiple dose bioequivalence studies are required for the approval of generic prolonged-release products, but they are not required by the US-FDA. In order to investigate if the multiple dose bioequivalence studies are necessary, the bioequivalence studies assessed in the Spanish Agency for Medicines and Health Care Products in the last 10 years were searched to find all reasons for rejection and identify those cases where the multiple dose study had failed to show bioequivalence and the single dose study had shown bioequivalence. In these latter cases, the plasma concentration at the end of the dosing interval (C(τ)) in the single dose study was assessed to investigate its sensitivity to predict non-bioequivalence in the steady state. The search identified six cases where the non-equivalence in the multiple dose study was not detected by the corresponding single dose study. C(τ) was not able to detect the difference in five cases and in general it was more variable than conventional metrics. In conclusion, the multiple dose bioequivalence study is necessary to ensure therapeutic equivalence and the use of C(τ) would be counterproductive, increasing the sample size of the studies without enough sensitivity to detect differences in the steady state.
authors: División de Farmacología y Evaluación Clínica, Subdirección de Medicamentos de Uso Humano, Agencia Española de Medicamentos y Productos Sanitarios, C/Campezo 1, Edificio 8, Planta 2 Oeste, E-28022 Madrid, Spain. agarciaa@aemps.es
authors: Alfredo
authors: A
authors: García-Arieta
authors: Susana
authors: S
authors: Morales-Alcelay
authors: Marta
authors: M
authors: Herranz
authors: José María
authors: JM
authors: de la Torre-Alvarado
authors: Antonio
authors: A
authors: Blázquez-Pérez
authors: Ma Luisa
authors: ML
authors: Suárez-Gea
authors: Covadonga
authors: C
authors: Alvarez
mesh_terms: D002626:Chemistry, Pharmaceutical; D003692:Delayed-Action Preparations; D017277:Drug Approval; D004339:Drug Compounding; D016568:Drugs, Generic / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D013030:Spain; D013678:Technology, Pharmaceutical / Q000379:methods; D013810:Therapeutic Equivalency
chemical_list: D003692:Delayed-Action Preparations; D016568:Drugs, Generic