2. How does fed and fasted state effect GI simulation?(5)

 The presence of food may affect drug absorption via a variety of mechanisms;
by impacting GI tract physiology (e.g. food- induced changes in gastric
emptying time, gastric pH, intestinal fluid composition, hepatic blood flow),
drug solubility and dissolution, and drug permeation.

 A study conducted to observe human food effect revealed that 67% of BCS
Class I compounds in the data set showed no food effect, 71% of the BCS Class
II compounds had a positive food effect, 61% of BCS Class III compounds
showed a negative food effect and Class IV compounds in this dataset, a large
majority (73%) showed a positive food effect.

 One alternative to animal experiments is to simulate food effects in humans
using physiologically based absorption models.

 Considering that these models are built based on a prior knowledge of GI
physiology in the fasted and fed states, they are able to describe the kinetics of
drug transit, dissolution, and absorption on the basis of drug- specific features
such as permeability, biorelevant solubility, ionization constant(s), dose,
metabolism and distribution data,etc.

 Food effects on drug absorption are generally better predicted when using
biorelevant media containing bile salts and lecithin as compared to the
traditional USP compendial media such as simulated gastric fluid (SGF) and
simulated intestinal fluids (SIF).

 Jones et al. developed physiologically based pharmacokinetic models (PBPK) in
GastroPlus® using permeability, solubility, metabolism and distribution data for
each compound.

 Biorelevant solubilities were measured in different media: simulated human
gastric fluid for the fasted and fed state, simulated human intestinal fluid for
the fasted, fed, and high- fat state, and simulated human colonic fluid for the
upper and the lower colon.

 The effect of food was simulated by changing physiological parameters and the
food effect for each drug was estimated by comparing AUC or Cmax between
fasted, fed, and/or high- fat conditions.

 It was concluded that biorelevant solubility tests, in conjunction with
physiologically based absorption modeling, can be used to predict food effects
caused by solubility and dissolution rate limitations, and/or degradation.

 It is, however, difficult to design a universal simulated fed state media for use
with all compounds because the composition of in vivo fed state fluids is highly
dependent on the ingested meal itself.