title: Analysis of level A in vitro-in vivo correlations for an extended-release formulation with limited bioavailability.
abstract: A two-stage, numerical deconvolution approach was employed to develop level A in vitro-in vivo correlations using data for three formulations of an extended-release oral dosage form. The in vitro dissolution data for all formulations exhibited near-complete dissolution within the time frame of the test. The pharmacokinetic concentration-time profiles for 16 subjects in a cross-over study demonstrated notably limited bioavailability for the slowest formulation. These data were used as the basis for the IVIVC model development. Two models were identified that satisfied the nominal requirements for a conclusive internal predictability of the IVIVC, provided that all three formulations were used as internal datasets. These were a simple linear model with absorption cut-off and a piecewise-linear variable absorption scale model. A subsequent cross-validation of the models' robustness indicated that neither model predicted satisfactorily the pharmacokinetic characteristics of all formulations in a conclusive manner. The piecewise-linear variable absorption scale model provided the most accurate results, particularly with respect to the prediction of the slowest formulation's pharmacokinetic metrics. But this latter model also involved additional free parameters compared with the simple linear model with absorption cut-off. It is argued that more complex IVIVC models with extra parameterization require comprehensive validation to ascertain the accuracy and robustness of the model. In order to achieve this, it is necessary to ensure a complete suite of supporting datasets for internal and external validation, irrespective of the mathematical approach used subsequently to develop the IVIVC.
authors.affiliation: Food and Drug Administration, Silver Spring, MD 20993, USA. maziar.kakhi@fda.hhs.gov
authors.forename: Maziar
authors.initials: M
authors.lastname: Kakhi
authors.forename: Patrick
authors.initials: P
authors.lastname: Marroum
authors.forename: Jason
authors.initials: J
authors.lastname: Chittenden
mesh_terms: D000042:Absorption; D000284:Administration, Oral; D001682:Biological Availability; D001702:Biopharmaceutics / Q000379:methods; D003692:Delayed-Action Preparations / Q000493:pharmacokinetics*; D017277:Drug Approval / Q000379:methods; D004335:Drug and Narcotic Control; D006801:Humans; D016014:Linear Models; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000592:standards; D011786:Quality Control; D012995:Solubility
chemical_list: D003692:Delayed-Action Preparations; D004364:Pharmaceutical Preparations
keywords: extended-release dosage form; internal/external validation; level A IVIVC; model robustness; numerical deconvolution