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Biliary Excretion–Mediated Food Effects and Prediction

  • Research Article
  • Theme: Predicting the Effects of Food Intake on Pharmacokinetics : Current Status and Future Perspectives
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Abstract

Many orally administered drugs with negative food effects (i.e., lower exposure under fed conditions) are often primarily or partially eliminated by biliary excretion. The aim of this study is to assess the potential correlation between a negative food effect and biliary excretion. Correlation analysis was conducted using a training dataset containing 27 drugs which met the following criteria: (1) immediate-release formulations, (2) shows a negative food effect, (3) > 10% biliary clearance, and (4) does not undergo extensive metabolism. A correlation between fed-state biliary clearance (CLb,fed) and fasted-state biliary clearance (CLb,fast) (y = 1.81*x, R2 = 0.68) was observed. The 1.8-fold increase in biliary clearance was then used as a correction factor to improve physiologically based pharmacokinetic (PBPK) prediction of food effects for 12 test drugs. The mean deviations of predicted fed/fasting AUC ratio and Cmax ratio from clinically observed values were reduced from 32.4 to 17.2% and from 63.3 to 54.3%, respectively. In contrast to the positive food effects on most biopharmaceutics classification system (BCS) class II drugs for which food-stimulated bile flow increases drug solubility and absorption, our results suggest that the elimination of biliary excreted drugs is increased by food-stimulated bile flow, resulting in negative food effects.

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Acknowledgments

We thank Dr. Xinning Yang from the FDA, Office of Clinical Pharmacology, for his comments and suggestions in the revision of this manuscript.

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This article reflects the views of the authors and should not be construed to represent FDA’s views or policies.

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This work was supported by the FDA Summer Intern Program and Critical Path Funding Program.

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Authors and Affiliations

  1. Food and Drug Administration (FDA), Office of Clinical Pharmacology, 10903 New Hampshire Ave, Silver Spring, Maryland, 20993, USA

    Jingcheng Xiao, Doanh Tran, Xinyuan Zhang, Shirley Seo & Peng Zou

  2. College of Pharmacy, University of Michigan, 428 Church St, Ann Arbor, Michigan, 48109, USA

    Jingcheng Xiao & Haojie Zhu

  3. School of Pharmacy, Husson University, 1 College Circle, Bangor, Maine, 04401, USA

    Tao Zhang

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Xiao, J., Tran, D., Zhang, X. et al. Biliary Excretion–Mediated Food Effects and Prediction. AAPS J 22, 124 (2020). https://doi.org/10.1208/s12248-020-00509-1

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