Analysis of level A in vitro-in vivo correlations for an extended-release formulation with limited bioavailability

• Published in: Biopharmaceutics & drug disposition Vol. 34; no. 5; pp. 262 - 277
• Main Authors: Kakhi, Maziar, Marroum, Patrick, Chittenden, Jason
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.07.2013; Wiley Subscription Services, Inc
• Subjects: Absorption; Administration, Oral; Biological Availability; Biopharmaceutics - methods; Delayed-Action Preparations - pharmacokinetics; Drug and Narcotic Control; Drug Approval - methods; extended-release dosage form; Humans; internal/external validation; level A IVIVC; Linear Models; model robustness; Models, Biological; numerical deconvolution; Pharmaceutical Preparations - chemistry; Pharmaceutical Preparations - standards; Quality Control; Solubility; extended-release dosage form; model robustness; level A IVIVC; numerical deconvolution; internal/external validation
• ISSN: 0142-2782; 1099-081X; 1099-081X
• DOI: 10.1002/bdd.1820

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. Copyright © 2013 John Wiley & Sons, Ltd.