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Biliary Excretion-Mediated Food Effects and Prediction.
Jingcheng Xiao1,2, Doanh Tran1, Xinyuan Zhang1
1Food and Drug Administration (FDA), Office of Clinical Pharmacology, 10903 New Hampshire Ave, Silver Spring, Maryland, 20993, USA.
The AAPS Journal
|September 27, 2020
Summary
Food intake decreases drug exposure for some medications primarily eliminated by biliary excretion. This study found increased biliary excretion with food, explaining these negative food effects and improving drug modeling.
Area of Science:
- Pharmacokinetics
- Drug Metabolism and Elimination
- Drug Interactions
Background:
- Many orally administered drugs exhibit reduced exposure when taken with food, a phenomenon known as a negative food effect.
- These drugs are often cleared via biliary excretion, suggesting a link between food intake and this elimination pathway.
Purpose of the Study:
- To investigate the correlation between negative food effects and biliary excretion for orally administered drugs.
- To evaluate the impact of food-stimulated bile flow on drug elimination through biliary pathways.
Main Methods:
- Correlation analysis was performed on a training dataset of 27 drugs with negative food effects, significant biliary clearance, and minimal metabolism.
- Physiologically based pharmacokinetic (PBPK) models were refined using a correction factor derived from the observed correlation to predict food effects.
Main Results:
- A significant positive correlation was found between fed-state and fasted-state biliary clearance (R² = 0.68), with an observed 1.8-fold increase in clearance under fed conditions.
- Applying this correction factor improved PBPK predictions of food effects, reducing mean deviations in AUC and Cmax ratios by 15.2% and 9.0%, respectively.
Conclusions:
- Food-stimulated bile flow increases biliary excretion, leading to reduced systemic exposure (negative food effect) for drugs primarily eliminated via this route.
- This finding contrasts with positive food effects seen in some BCS Class II drugs where food enhances absorption.
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