Abstract

The bioavailability of an orally administered small molecule is often dictated by drug-specific
physicochemical characteristics and is influenced by many biological processes. For example, in fed or
fasted conditions, the transit time within the gastrointestinal tract can vary, confounding the ability to
predict the oral absorption. As such, the effects of food on the pharmacokinetics of compounds in the
various biopharmaceutics classification system (BCS) classes need to be assessed. The consumption
of food leads to physiological changes, including fluctuations in the gastric and intestinal pH, a delay
in gastric emptying, an increased bile secretion, and an increased splanchnic and hepatic blood flow.
Despite the significant impact of a drug’s absorption and dissolution, food effects have not been fully
studied and are often overlooked. Physiologically-based pharmacokinetic (PBPK) models can be
used to mechanistically simulate a compound’s pharmacokinetics under fed or fasted conditions,
while integrating drug properties such as solubility and permeability. This review discusses the PBPK
models published in the literature predicting the food effects, the models’ strengths and shortcomings,
as well as future steps to mitigate the current knowledge gap. We observed gaps in knowledge which
limits the ability of PBPK models to predict the negative food effects and food effects in the pediatric
population. Overall, the further development of PBPK models to predict food effects will provide a
mechanistic basis to understand a drug’s behavior in fed and fasted conditions, and will help enable
the drug development process.

By Cheng L, Wong H