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Using Physiologically Based Pharmacokinetic (PBPK) Modeling to Evaluate the Impact of Pharmaceutical Excipients on Oral Drug Absorption: Sensitivity Analyses

  • Research Article
  • Theme: Effects of Pharmaceutical Excipients on the Function of Transporters and Cytochrome P450 in Gastrointestinal Tract and Or
  • Published:
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Abstract

Drug solubility, effective permeability, and intestinal metabolism and transport are parameters that govern intestinal bioavailability and oral absorption. However, excipients may affect the systemic bioavailability of a drug by altering these parameters. Thus, parameter sensitivity analyses using physiologically based pharmacokinetic (PBPK) models were performed to examine the potential impact of excipients on oral drug absorption of different Biopharmaceutics Classification System (BCS) class drugs. The simulation results showed that changes in solubility had minimal impact on Cmax and AUC0-t of investigated BCS class 1 and 3 drugs. Changes in passive permeability altered Cmax more than AUC0-t for BCS class 1 drugs but were variable and drug-specific across different BCS class 2 and 3 drugs. Depending on the drug compounds for BCS class 1 and 2 drugs, changes in intestinal metabolic activity altered Cmax and AUC0-t. Reducing or increasing influx and efflux transporter activity might likely affect Cmax and AUC0-t of BCS class 2 and 3 drugs, but the magnitude may be drug dependent. Changes in passive permeability and/or transporter activity for BCS class 2 and 3 drugs might also have a significant impact on fraction absorbed and systemic bioavailability while changes in intestinal metabolic activity may have an impact on gut and systemic bioavailability. Overall, we demonstrate that PBPK modeling can be used routinely to examine sensitivity of bioavailability based on physiochemical and physiological factors and subsequently assess whether biowaiver requirements need consideration of excipient effects for immediate release oral solid dosage forms.

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Acknowledgments

The authors would like to thank Dr. Peng Zou (FDA) for discussion and providing comments on this project.

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Authors and Affiliations

  1. Division of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, US Food and Drug Administration, Silver Spring, Maryland, USA

    Edwin Chiu Yuen Chow, Arjang Talattof, Eleftheria Tsakalozou, Jianghong Fan, Liang Zhao & Xinyuan Zhang

  2. 10903 New Hampshire Ave., Bldg. 75, Room 4690, Silver Spring, Maryland, 20993, USA

    Edwin Chiu Yuen Chow, Arjang Talattof, Eleftheria Tsakalozou, Jianghong Fan, Liang Zhao & Xinyuan Zhang

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  1. Edwin Chiu Yuen Chow
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  2. Arjang Talattof
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Correspondence to Xinyuan Zhang.

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Guest Editor: Peng Zou

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Chow, E.C.Y., Talattof, A., Tsakalozou, E. et al. Using Physiologically Based Pharmacokinetic (PBPK) Modeling to Evaluate the Impact of Pharmaceutical Excipients on Oral Drug Absorption: Sensitivity Analyses. AAPS J 18, 1500–1511 (2016). https://doi.org/10.1208/s12248-016-9964-4

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