Project Summary / Abstract
Physiologically-based pharmacokinetic (PBPK) models can separate drug/formulation
characteristics from the underlying physiology and are well positioned to predict PK including
inter-individual variability. A further advantage of Population PBPK is the ability to
extrapolate from a model validated for a particular drug/formulation in one population (e.g.,
healthy volunteer) to another population (e.g., elderly or paediatric) provided the
physiological differences are sufficiently well characterised. The Simcyp Population-Based
Simulator includes a sophisticated oral absorption module which can simulate clinical trials
predicting inter-individual variability rather than just an ‘average person’.
This project aims to incorporate state-of-the art mechanistic models for handling
supersaturation and precipitation (S&P) properties of poorly soluble drug products. S&P
properties can have a major influence on the overall bioavailability of such compounds.
Thus, the ability to anticipate these properties from in vitro experiments and extrapolate to in
vivo outcomes can be critical to a drug development program; where appropriate formulation
strategies can be followed to either prevent precipitation or mitigate its impact. The PBPK
models require: drug and formulation-specific information; mechanistic algorithms for not
only precipitation itself (such as, but not only, classical nucleation theory) but also the
numerous other processes occurring within the gastrointestinal tract and the associated
physiological and anatomical parameters and their inter-individual variability, which play an
important role in supersaturation/precipitation behaviour in vivo. This includes gastric and
small intestinal luminal fluid volumes; gastrointestinal transit times of fluids, fine particles and
intact single unit dosage forms; regional luminal pH; fluid viscosity, effect of excipients, etc.
The new mechanistic models are to be incorporated into both the Simcyp platform itself and
crucially into separate complementary tools for modelling appropriate in vitro experiments
such as media transfer experiments. This parallel implementation is essential for
understanding, testing and parameterising the models. The existing standalone Simcyp In
Vitro Analysis (SIVA) toolkit provides an ideal framework within which to add new modelling
algorithms. At least eleven model drug products dosed under various conditions and
exemplifying different mechanisms of supersaturation and precipitation are considered to be
used for performance verification of the developed models and physiologies the results of
which will be disseminated to the general scientific community through appropriate channels.