Mechanistic Model-based Analysis of Biopharmaceutics Experiments – Application of In Vitro-In Vivo Extrapolation (IVIVE) Techniques within a PBPK Modeling Framework

Author(s): Shriram Pathak, Kerstin Frank, Nikunjkumar Patel, Bo Liu, Masoud Jamei, David Turner
  • In vitro dissolution testing is a critical component of drug product development and is often used as a surrogate for in vivo performance.
  • While the range of (USP) standard methods have been developed and tested for many years, no single dissolution test or apparatus comprehensively maps the in vivo behaviour of the range of compound classes and sub-classes therein.
  • Moreover, in the case of poorly soluble, low pKa basic drugs, handling supersaturation and precipitation related attributes, mainly relevant upon transfer of the drug from the low pH stomach into unfavourable
    elevated pH in the small intestine, is very important and needs to be accounted for during in vitro testing.
  • Recently, advances have been made in in vitro experimental designs to better mimic the complex drug dissolution and precipitation kinetics in the GI lumen.
  • The two-phase dissolution setup is one such attempt, undertaken to simulate drug dissolution in the near sink conditions expected in vivo for poorly soluble, highly permeable BCS II compounds .
  • The purpose of this work was to demonstrate how mechanistic modelling of dissolution experiments can help to assess effectively the physiological relevance of these methods for extrapolating to in vivo simulations via a PBPK modelling approach.

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