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improved solubilization due to higher bile salt and lipid concentrations.
Negative food effects are mostly seen for hydrophilic drugs, where food
impedes permeation (Gu et al., 2007). One of the frequently used
approaches to assess the effect of food on oral drug absorption involves
animal studies (Humberstone et al., 1996; Paulson et al., 2001; Wu et al.,
2004; Xu et al., 2012). However, due to the fact that physiological factors
are species dependent, the magnitude of food effect for a given compound
across species is usually different, thus complicating the prediction of
food effects in humans (Jones et al., 2006b). 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-specifi c features such as permeability, biorelevant
solubility, ionization constant(s), dose, metabolism and distribution data,
etc. Gastroplus™ default physiology parameters, which differ between
fasted and fed states, are given in Table 6.9.
Several studies have confi rmed the usefulness of the
in silico
modeling
approach to assess food effects on oral drug absorption. For example,
Jones et al. (2006b) incorporated biorelevant solubility and degradation
data into the GastroPlus™ absorption model to predict plasma profi les in
fed, fasted, and/or high-fat conditions for six model compounds.
Biorelevant solubilities were measured in different media: simulated
human gastric fl uid for the fasted and fed state, simulated human
intestinal fl uid for the fasted, fed, and high-fat state, and simulated human
colonic fl uid for the upper and the lower colon. The effect of food was
GastroPlus™ (version 8.0) interpretation of changes in
human physiology between fasted and fed states
Table 6.9
Physiological parameter
Fasted
Fed
Stomach pH
1.3
4.9
Stomach transit time (h)
0.25
1.00
Stomach volume (mL)
50
1000
Duodenum pH
6.0
5.4
Jejunum 1 pH
6.2
5.4
Jejunum 2 pH
6.4
6.0
Hepatic blood fl ow (L/min)
1.5
2.0
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