title: Assessment of the Regulatory Methods for the Comparison of Highly Variable Dissolution Profiles.
abstract: The objective is to compare the performance of dissolution-profile comparison methods when f2is inadequate due to high variability. The 90% confidence region of the Mahalanobis distance and the 90% bootstrap confidence interval (CI) of the f2similarity factor (f2-bootstrap) were explored. A modification of the Mahalanobis distance (new D-Mahalanobis) in which those points >85% were not taken into account for calculation was also used. A population kinetic approach in NONMEM was used to simulate dissolution profiles with the first-order or Weibull kinetic models. The scenarios were designed to have clearly similar, clearly non-similar or borderline situations. Four different conditions of variability were established: high (CV = 20%) and low variability (CV = 5%) for inter-tablet (IIV) and inter-batch variability (IBV) associated to the dissolution parameters (kdor MDT) using an exponential model. Forty-four (44) scenarios were simulated, considering different combinations of IIV, IBV and typical dissolution parameters. The dissolution profiles simulated using a first-order model modified the profile slope. The Weibull model allows profiles with different shapes and asymptotes and crossing each other. The results show that the f2-bootstrap is the most adequate method in cases of high variability. The method based on the 90% confidence region of the Mahalanobis distance (D-Mahalanobis) is not able to detect large differences that can be detected simply with f2(i.e. low specificity and positive predictive value due to false positives). The new D-Mahalanobis exhibits superior sensitivity to detect differences (i.e. specificity as a diagnostic test), but it is not as good as the f2-bootstrap method.
authors: Department of Engineering, Pharmacy and Pharmaceutical Technology Area, Miguel Hernandez University, Elche, Spain.
authors: Victor
authors: V
authors: Mangas-Sanjuan
authors: Analysis and Control Department, University of Los Andes, Mérida, Venezuela.
authors: Sarin
authors: S
authors: Colon-Useche
authors: Department of Engineering, Pharmacy and Pharmaceutical Technology Area, Miguel Hernandez University, Elche, Spain.
authors: Isabel
authors: I
authors: Gonzalez-Alvarez
authors: Department of Engineering, Pharmacy and Pharmaceutical Technology Area, Miguel Hernandez University, Elche, Spain.
authors: Marival
authors: M
authors: Bermejo
authors: Pharmacokinetics and Generic Medicines, Division of Pharmacology and Clinical Evaluation, Department of Human Use Medicines, Agencia Española de Medicamentos y Productos Sanitarios (AEMPS), C/ Campezo 1. Edificio 8, Planta 2 Oeste, 28022, Madrid, Spain. agarciaa@aemps.es.
authors: Alfredo
authors: A
authors: Garcia-Arieta
mesh_terms: D008962:Models, Theoretical; D010599:Pharmacokinetics; D012995:Solubility
keywords: Mahalanobis distance; dissolution profile comparison; f 2 bootstrap; f 2 similarity factor; in vitro dissolution