In vitro–in vivocorrelations: general concepts, methodologies and regulatory applications

Abstract

The major objective of in vitro-in vivo correlations is to be able to use in vitro data to predict in vivo performance serving as a surrogate for an in vivo bioavailability test and to support biowaivers. Therefore, the aims of this review are: (i) to clarify the factors involved during bio-predictive dissolution method development; and (ii) the elements that may affect the mathematical analysis in order to exploit all information available. This article covers the basic aspects of dissolution media and apparatus used in the development of in vivo predictive dissolution methods, including the latest proposals in this field as well as the summary of the mathematical methods for establishing the in vitro-in vivo relationship and their scope and limitations. The incorporation of physiological relevant factors in the in vitro dissolution method is essential to get accurate in vivo predictions. Standard quality control dissolution methods do not necessarily reflect the in vivo behavior, so they rarely are useful for predicting in vivo performance. The combination of physiological based dissolution methods with physiological-based pharmacokinetics models incorporating gastrointestinal variables will lead to robust tools for drug and formulation development, nevertheless their regulatory use for biowaiver application still require harmonization of the mathematical methods proposed and more detailed recommendations about the procedures for setting up dissolution specifications.

Development of a Dissolution Method for Gliclazide Modified-Release Tablets Using USP Apparatus 3 with <i>in Vitro–in Vivo</i> Correlation

“…An overlap of the in vivo absorbed fraction and in vitro dissolved fraction curves was clearly observed and is reflected by the establishment of a point-to-point IVIVC (level A), indicating that the dissolution test conditions were able to simulate the in vivo performance. 24,[41][42][43] The results also demonstrate the ability of USP3 to mimic GIT conditions for MR dosage forms 44) and the suitability of this apparatus for the development of in vitro dissolution assays for GLZ MR dosage forms.…”

“…22,25,26) This correlation is considered more informative than the other levels of correlation and is useful from a regulatory point of view. 24) Because it provides greater similarity to the conditions a particular MR dosage form is exposed to in vivo, the use of a USP apparatus 3 seems more appropriate and has been demonstrated to be promising for the development of biorelevant dissolution methodologies. 20) Considering that the low solubility of GLZ can be the rate limiting step for its dissolution and absorption, a prediction of its in vivo behavior based on a dissolution test using biorelevant media should lead to a more relevant IVIVC.…”

“…20,21) To describe a relationship between in vitro characteristics of a dosage form and the in vivo response, a predictive mathematical model is used to define the in vitro-in vivo correlation (IVIVC) level. [22][23][24] A level A IVIVC is the highest correlation level that can be achieved and represents a point-to-point relationship between in vitro dissolution and in vivo absorption. 22,25,26) This correlation is considered more informative than the other levels of correlation and is useful from a regulatory point of view.…”

Physiologically-based pharmacokinetic models: approaches for enabling personalized medicine

“…For a BSC Class II drug, solubility is low and likely to be pH dependent within the physiological range [172,173]. Class II drugs can be separated further into subclasses dependent on the drug’s pKa : weakly acidic ( pKa ≤ 5, Class IIa), weakly basic ( pKa ≥ 6, Class IIb), and neutral (Class IIc).…”

“…First an in vitro-in vivo correlation (IVIVC) is needed to link the in vivo release profile to in vitro dissolution data. A point-to-point relationship is needed to predict the entirety of the in vitro dissolution profile for future formulations and thus a Level A IVIVR will be required [173,189]. Once the target in vitro dissolution profile is determined, experimental studies can be completed to determine the formulation and process conditions that are needed to achieve the desired rate.…”